CN105130966B - Alkynyl compounds and its application method and purposes - Google Patents

Abstract

The present invention relates to a new class of alkynyl compounds and using its free form or pharmaceutically acceptable salt and dosage form as the purposes for the drug for treating the extremely relevant disorder of PI3- kinases or disease.The present invention also relates to the pharmaceutical composition comprising the compounds of this invention, and use the medicine composite for curing mammal, the especially purposes of the extremely relevant human disorder for the treatment of PI3- kinases or disease, such as, the treatment of immunity and inflammatory disease that the PI3- kinases to play a major role in leukocyte function is adjusted, and proliferative diseases relevant to PI3- kinase activity, the including but not limited to treatment of leukaemia and solid tumor.

Description

Alkynyl compounds and its application method and purposes

Invention field

The invention belongs to drug fields, and in particular to a kind of noval chemical compound as kinase activity inhibitor prepares them Method, the pharmaceutical composition comprising the compound and the compound and its pharmaceutical composition treating a variety of different diseases Application in disease.More specifically, compound of the present invention can be used as phosphoinositide 3-kinase family (PI3- Kinases, PI3Ks, such as PI3K δ, PI3K α, PI3K β and PI3K γ) activity or function inhibitor.

Background of invention

Phosphoinositide 3-kinase (PI3- kinases or PI3Ks), as a family of lipid kinase, many cells into Journey plays important adjustment effect in breeding and differentiation such as the survival of cell.As receptor tyrosine kinase (RTKs) and G Major influence factors in the conduction of the protein-coupled receptor downstream (GPCRs), by generating phosphatide, PI3Ks will come from all kinds of growths The signal transduction of factor and the factor to intracellular, activate Ser-ine-threonine protein kinase AKT (also referred to as protein kinase B (PKB)) and Other downstream passages.Tumor suppressor gene or PTEN (homologous phosphatase-tensin) are most important in PI3K signal path Reversed regulator (" Small-molecule inhibitors of the PI3K signaling network. " Future Med Chem.,2011,3,5,549-565)。

Up to the present, the PI3Ks of 8 kinds of mammals has been identified, gene order, structure, adapter molecule, table are based on It reaches, the difference of activation mechanism and substrate can be divided into three classes (I, II and III).It wherein, again can be according to letter according to I class PI3Ks Number access and regulatory protein are divided into two class of IA and IB.IA class PI3Ks (PI3K α, PI3K β and PI3K δ) is by catalytic subunit P110 (being p110 α, p110 β and p110 δ respectively) and regulator subunit p85 (such as: p85 α, p85 β, p55 δ, p55 α and p50 α) The heterodimeric nanocrystal composition of composition.P110 subunit with catalytic activity using ATP phosphorylation phosphatidylinositols (PI, PtdIns), PI4P and PI (4,5) P2.The response of these signals is usually by receptor tyrosine kinase (RTKs) transmitting.IB class PI3K γ signal be by g protein coupled receptor (GPCRs) transmit, be made of catalytic subunit p110 γ, with p110 γ Relevant adjusting subunit is different with IA class hypotype.

The signal path in phosphatide relevant to the function of effector enzyme and adjusting be I class PI3Ks (e.g., PI3K δ, PI3Kdelta after) being activated, second messenger is generated on membrane phospholipid.Membrane phospholipid PI (4,5) P2 is converted conduct by I class PI3Ks PI (3,4,5) P3 of second messenger.PI and PI (4) P is also the substrate of PI3K, they can also be phosphorylated and convert respectively For PI3P and PI (3,4) P2.In addition, these phosphoinositides can also pass through the catalysis of 5 '-specificity and 3 '-specificity phosphatases Effect is converted to other phosphoinositides.In this way, direct or indirect two kinds of the generation of activity of PI3K enzyme signal transduction in the cell In approach as the 3 '-phosphoinositide hypotypes of second messenger (Nature Reviews Molecular Cell Biology, 2010,11,329)。

The expression way of PI3K α and PI3K two kinds of hypotypes of β is generally existing, however mainly found in leucocyte The expression way of both hypotypes of PI3K δ and PI3K γ can be more restricted.PI3K δ and PI3K γ relatively limited expression way, In addition to showing that the accumulative data to mice study also can show that the two hypotypes in adaptability and innate immune system Important function (J.Med.Chem., 2012,55,20,8559-8581).

In B and T cell, PI3Ks passes through the Tec family of activator protein tyrosine kinase, plays a significant role, the family Race includes the Bruton ' s tyrosine kinase (BTK) in B cell and the proleulzin in T cell-induction type T- cell kinase (ITK).Once PI3K is activated, BTK or ITK transposition to plasma membrane, they are then by Src tyrosine phosphorylation there.The ITK of activation Main target first is that Phospholipase C-gamma (PLC γ 1), is hydrolyzed to PI (3,4,5) P3 for PI (4,5) P2 and starts to make cell Interior calcium level improves and can activate the protein kinase C diglyceride (DAG) in the T cell of activation.

PI3K δ kinases, which completely knocks in (knock-in) mouse, can also survive, and their phenotype is limited to immune signal The defect (Okkenhaug et al., Science, 2002,297, p.1031-4) of conduction.These transgenic mices provide The understanding in depth of function of the PI3K δ in B- cell and T- cellular signal transduction.Especially, PI3K δ for CD28 PI (3, 4,5) P3 forms downstream and/or T cell receptor (TCR) signal is required.The important function in the PI3K signal transduction downstream of TCR It is the activation to Akt, a variety of different transcription factor phosphoric acid for making the anti-apoptotic factor and being generated for cell factor Change.As a result, the T cell with inactive PI3K δ lacks in terms of being proliferated with Th1 and Th2 cytokine secretion.T cell is logical Cross magnitude and duration that the activation of CD28 reduces TCR by the threshold value of antigenic activation and increase breeder reaction.These effects are all Being includes being situated between to PI3K δ-dependence increase in the transcription of IL2 (an important t cell growth factor) by many genes It leads.

Therefore, PI3K inhibitor is expected via it in adjusting and respiratory disease, such as asthma, COPD and cystic fibrosis Effect in associated T- cell-mediated inflammatory reaction provides treatment benefit.Additionally, there are the therapies for having T- cell to be oriented to can There is provided save Corticosteroids (corticosteroid sparing) characteristic instruction (Lancet, 1992,339, p.324- 8) it, prompts it or merges as independent (standalone) or with sucking or oral glucocorticosteroid, it is possible to provide Useful therapy in respiratory disease.PI3K inhibitor can also be with other routine treatments, such as long acting beta-2-agonists (LABA) one It rises and is used for asthma.

In vascular system, PI3K δ is expressed by endothelial cell, and through these cells of adjusting in responding with TNF α Pre- attachment (neutrophil) state participation be neutrophil migration (trafficking) (Blood, 2004,103,9, p.3448).PI3K δ can be proved in the TNF α of endothelial cell by Akt phosphorylation and the active pharmacology inhibiting effect of PDK1 The effect of the signal transduction of induction.In addition, PI3K δ is related to vascular permeability and air flue tissue edema by VEGF access (Allergy Clin.Immunol.,2006,118,2,p.403).These observations show that PI3K δ inhibits additional in asthma Benefit, the benefit are reduced and are realized with the associated leucocyte spilling of asthma and vascular permeability by merging.In addition, PI3K δ activity The mast cell function of both in vitro and in vivo is needed (Nature, 2004,431, p.1007；J.Immunol., 2008,180,4, p.2538), also prompt PI3K inhibition should be to allergic reaction indication, such as asthma, allergic rhinitis and spy Answer atopic dermatitis that there is treatment benefit.

PI3K δ offers in B cell proliferation, antibody-secreting, B- cellular antigens and the conduction of IL-4 receptor signal, B cell antigen Effect in function also obtain determine (J.Immunol., 2007,178,4, p.2328-35；Blood,2006,107,2,p.642- 50), and show it in autoimmune disease, such as the effect in rheumatic arthritis or systemic loupus erythematosus.Therefore, PI3K inhibitor also has a better effect above-mentioned indication tool.

Agar glycosyl of the neutrophil cell that the pharmacological inhibiting effect of PI3K δ inhibits fMLP- to rely on to ICAM coating The chemotaxis (Sadhu etc., J.Immunol., 2003,170,5, p.2647-54) of matter integrin-dependence deflection system. The inhibition of PI3K δ adjusts neutrophil activation, adherency and migration, without influence neutrophil cell mediation to golden yellow Staphylococcic phagocytosis and bactericidal activity (Sadhu etc., Biochem.Biophys.Res.Commun, 2003,308,4, p.764-9).In short, the data shows that PI3K δ inhibition should be unable to inhibit neutrophilia required for defending congenital immunity comprehensively Granulocyte function.Effect of the PI3K δ in neutrophil cell is provided including treatment tissue remodeling (such as COPD and rheumatic pass Section is scorching) inflammation disease more room.

PI3K γ has been identified as the medium of G β-γ-dependence adjusting of JNK activity, and G β-γ is heterotrimer The subunit (J.Biol.Chem., 1998,273,5, p.2505-8) of G-protein (heterotrimeric G proteins).Most Closely, (Laffargue etc., Immunity, 2002,16,3, p.441-51), which has been described PI3K γ and pass through a variety of G (i)-, is coupled Receptor transfer (relays) inflammatory signals (inflammatory signals), and it is to mast cell function, He Bai Stimulant in cell and immunology context is important, and the stimulant includes such as cell factor, chemotactic factor (CF), gland Glycosides, antibody, integrin, agglutination factor, growth factor, virus or hormone (J.Cell Sci., 2001,114 (Pt 16), p.2903-10and Curr.Opinion Cell Biol.,2002,14,2,p.203-13)。

It has better understood now, the imbalance of oncogene and tumor suppressor gene, such as raw by increased cell Long and proliferation or increase cell survival promote malignant tumour to be formed.Now it is also known that road, is passed by the signal that PI3K family mediates Guiding path plays a significant role in the multiple cell processes for including proliferation and existence, and the imbalance of these accesses is various Human cancer and Other diseases the origin cause of formation (Annual Rev.Cell Dev.Biol., 2001,17, p.615-675and J.Cell Science,2003,116,15,p.3037-3040)。

In addition, also there is good evidence to show that I class PI3K enzyme also directly or indirectly facilitates various human cancers Tumour 2002,2,7, p.489-501 (Vivanco and Sawyers, Nature Reviews Cancer) occurs.For example, The inhibition of PI3K δ for hematologic disorder, such as acute myelogenous leukemia have preferable therapeutic effect (Oncogene, 2006,25,50,p.6648-59).In addition, activated mutant and a variety of different other tumours in p110 α (PIK3CA gene), Such as colon cancer, breast cancer and lung cancer it is associated (Science, 2004,304,5670, p.554；Nature Reviews Cancer,2009,9,551)。

Also result of study shows, PI3K is related to the central sensitization (central in painful inflammatory disease Sensitization determination (J.of Neuroscience, 2008,28,16, p.4261-4270)).

Various retrovirus and DNA base activated viral PI3K access, as host during pre- preventing virus infection The mode of cell death and finally explore for its duplication host cell synthesis mechanism (V Virology, 2006,344,1, p.131-8and Nat.Rev.Microbiol.,2008,6,4,p.265-75).Therefore, PI3K inhibitor is in addition to more determining Outside oncolytic (oncolytic) and anti-inflammation indication, can also have ntiviral characteristic.These antivirus actions cause in disease Interesting prospect in the inflammation deterioration of poison induction.For example, common cold ERC group virus (HRV) causes the respiratory tract sense more than 50% Dye, but the complication of these infection can have more meaning in certain crowds.This is especially in respiratory disease, such as asthma or slow Property obstructive lung disease (COPD) in the case where especially so.The rhinovirus infection of epithelial cell cause PI3K rely on cell because Sub and chemokine secretion (J.Biol.Chem., 2005,280,44, p.36952).Disease is breathed during the inflammatory reaction and infection The deterioration of shape is related.Therefore, PI3K inhibitor can inhibit the immune response of (dampen) other benign virus amplification.It is most of HRV bacterial strain infects bronchial epithelial cell by initial combination to ICAM-1 receptor.Then, further pass through endocytosis Required by HRV-ICAM-1 compound is included in intracellular (internalised) and has shown that this measure has PI3K activity (J.Immunol.,2008,180,2,p.870-880).Therefore, PI3K inhibitor can also be by inhibiting cell entry host cell And prevent virus infection.

PI3K inhibitor can be used for reducing other types of respiratory infections, including fungal infection aspergillosis (Mucosal Immunol.,2010,3,2,p.193-205).In addition, the mouse that PI3K δ lacks is to by the very large Li Shiman of protozoon parasite Protozoon (Leishmania.major) infected with stronger resistance (J.Immunol., 2009,183,3, p.1921- 1933).In view of the effect to virus infection, these report prompt PI3K inhibitor can be used for treating various infection.

Studies have shown that PI3K inhibition also can promote regulatory T cells differentiation (Sauer etc., Proc.Natl.Acad.Sci.USA, 2008,105,22, p.7797-7802), prompt PI3K inhibitor can in autoimmunity or In allergic reaction indication, by inducing to the immunological tolerance of autoantigen or allergic reaction original for therapeutic purposes.Closely Phase, the insensitive association (Am.J.Respir.Crit.Care of glucocorticoid that PI3K δ hypotype has also been induced with smoking Med.,2009,179,7,p.542-548).Researches show that COPD patients for this, differently not to glucocorticosteroid response It is good, benefit can be obtained from the combination of PI3K inhibitor and glucocorticosteroid.

PI3K also has been directed to other respiratory diseases, such as idiopathic pulmonary fibrosis (IPF).IPF is fibre modification disease Disease, with progressive decreased lung function and due to caused by respiratory failure the death rate increase.In IPF, Circulating fibrocyte (circulating fibrocytes) is oriented to lung via Chemokine receptor CXCR4.Signal transduction of the PI3K for CXCR4 It is both required (Int.J.Biochem.and Cell Biol., 2009,41, p.1708-1718) with expression.Therefore, By reducing CXCR4 expression and blocking its effector functions, PI3K inhibitor can inhibit fibrocyte and raise to lung and thus Slow down fibrotic processes, a kind of disease of the less than foot therapy demand of height based on IPF.

3 Κ β of PI3K α and Ρ Ι is in the interior ambient stable and drug inhibition for maintaining molecular target relevant to cancer There is indispensable role (Maira et al., Expert Opin.Ther.Targets, 2008,12,223).

PI3K α also with the signal transduction of insulin and molecular growth path-dependent (Nature, 2006,441,366).ΡΙ3 The selective inhibitory of Κ δ hypotype is expected to be avoided that some potential side effects, such as hyperglycemia and metabolism or growth failure.

Some groups have been developed for the alternative cpd to PI3K γ, and effect is for autoimmune disease Immunosuppressor (Nature Reviews, 2006,5,903-918).It is worth noting that, AS 605240 has been demonstrated in class It is effective (Nature Medicine, 2005,11,936-943) in the mouse model of rheumatic arthritis, and in system It can postpone the breaking-out (Nature Medicine, 2005,11,933-935) of disease in the model of property lupus erythematosus.

PI3K δ selective depressant has been described recently.Most selective compound includes quinolinone purine inhibitors (PIK39 and IC87114), IC87114 inhibits PI3K δ in high nanomolar range (three digits), and has to PI3K δ and be greater than 100 times of selectivity has 52 times of selectivity to PI3K β, but lacks selectivity (about 8 times) to PI3K γ.It is to test Any protein kinase do not show active (Cell, 2006,125,733-747).Use PI3K δ alternative cpd or hereditary base Because controlling mouse (PI3K δ^D910A) prove, other than playing a crucial role in B and t cell activation, during PI3K δ is also related in part to Property leukocytoplania and sensitization neutrophil breathing, and cause antigen-IgE mediate mast cell threshing part resistance Disconnected (Blood, 2005,106,1432-1440；Nature,2002,431,1007-1011).Therefore, PI3K δ is closed as very much What the important medium of key inflammatory reaction occurred, the inflammatory reaction, which it is known that, participates in abnormal inflammatory disease, including but not limited to certainly Body immunological diseases and allergy.In order to support the viewpoint, produced from the experiment for using Genetic tools and medicament constantly Increased 1) PI3K δ verify data.Therefore, using PI3K δ alternative cpd IC87114 and PI3K δ^D910AMouse, Ali et al. Nature, 2002,431,1007-1011) verified PI3K δ play a crucial role in the mouse model of anaphylactia.? There is no in the case where function δ, passive cutaneous anaphylaxis (PCA) is substantially reduced, and can be attributed to antigen-IgE induction Mast cells activation and threshing reduction.In addition, the mouse model of the asthma in the airway inflammation induced using ovalbumin In, inhibit δ to have been demonstrated to significantly improve inflammation (FASEB, 2006,20,455-465) with IC87114.The use allergy of difference group In the same model of airway inflammation, using these data of compound in PI3K δ^D910AIt is mutually authenticated in mutant mice (Eur.J.Immunol.,2007,37,416-424)。

Need to be provided as the new PI3K inhibitor of good drug candidate.Specifically, it is preferable that compound should be with PI3K receptor effectively combines, while hardly showing compatibility to other receptors, and shows the function as agonist Activity.The compound should be fully absorbed by gastrointestinal tract, metabolic stability and have good pharmacokinetic property.When targeting maincenter When receptor in nervous system, they can freely pass through blood-brain barrier, and ought selectively target in peripheral neverous system Receptor when, they would not pass through blood-brain barrier.They answer nontoxicity and show few side effect.In addition, the ideal Drug candidate should with stabilization, non-hygroscopic and be easy prepare physical form exist.The compounds of this invention shows specific water The flat PI3K α for different paralogous (paralogs), the selectivity of beta, gamma and δ.In particular, showing specified level The selectivity for 3 Κ δ of Ρ Ι.

The compounds of this invention all has treatment potential to a series of illnesss being widely present, especially to autoimmune Disease, diseases associated with inflammation, anaphylactia, disease relevant to immune system or infection, airway disorders, such as asthma and chronic resistance Plug property tuberculosis (COPD), graft-rejection, tumour, such as hematopoietic system cancer or solid tumor.

The invention further relates to the treatment methods that other one or more pharmaceutical active compounds are used alone or in combination, this is controlled Treatment method includes the treatment of following disease or obstacle, respiratory disease, including asthma, Chronic Obstructive Pulmonary Disease (COPD) and spy Hair property pulmonary fibrosis (IPF)；Virus infection, including viral respiratory infection and viral respiratory disease deteriorate, and such as roar Asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Anaphylactia, including allergic rhinitis and spy Answer atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple sclerosis；Inflammatory disease, including inflammatory Enteropathy；Cardiovascular disease, including thrombosis and atherosclerosis (Future Med.Chem., 2013,5,4,479-492； Biochemical Society Transactions,2004,32,378)；Malignant hematologic disease；Neurodegenerative disease；Pancreas It is scorching；Multiple organ failure；Nephrosis；Platelet aggregation；Cancer；Sperm motility；Graft rejection；Graft rejection；Injury of lungs；And pain Bitterly, neuralgia, sugar including after pain relevant to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain, liver Urinate characteristic of disease neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain；Malignant hematologic disease, including Acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), the white blood of chronic myelognous Sick (CML), T cell acute lymphoblastic leukemia (T-ALL), B cell acute lymphoblastic leukemia (B-ALL), Fei Huoqi Golden lymthoma (NHL), B cell lymphoma, solid tumor (e.g., breast cancer).

Abstract of invention

The invention discloses a kind of noval chemical compounds can be used as kinase activity inhibitor, especially can be used as PI3- kinase activity Inhibitor.Compound as PI3- kinase inhibitor can be used for treating disease caused by unsuitable kinase activity, especially It is unsuitable disease caused by PI3- kinase activity, such as treating and preventing by the disease of PI3- kinases mechanisms mediate. Such disease includes respiratory disease, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)； Virus infection, including viral respiratory infection and viral respiratory disease deteriorate, such as asthma and COPD；Non-viral breathing Road infection, including aspergillosis and leishmaniasis；Allergic diseases, including allergic rhinitis and atopical dermatitis；Itself Immunity disease, including rheumatoid arthritis and multiple sclerosis；Inflammatory disease, including inflammatory bowel disease；Cardiovascular disease, packet Include thrombosis and atherosclerosis；Malignant hematologic disease；Neurodegenerative disease；Pancreatitis；Multiple organ failure；Nephrosis；Blood is small Plate aggregation；Cancer；Sperm motility；Graft rejection；Graft rejection；Injury of lungs；And pain, including with rheumatoid arthritis or Neuralgia, diabetic neuropathy, neuro-inflammatory after the relevant pain of osteoarthritis, backache, systemic inflammatorome pain, liver Property pain (wound), trigeminal neuralgia and central pain.

In some embodiments, the compounds of this invention shows that the selectivity of PI3- kinases be more than other kinases.

In other embodiment, the compounds of this invention can be effective inhibitor of PI3K δ.

In other embodiment, the compounds of this invention shows that the selectivity of PI3K δ be more than other PI3- kinases Type.

On the one hand, the present invention relates to a kind of compound, chemical combination shown in the compound or formula (I) for structure shown in formula (I) The stereoisomer of object, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:

Wherein: each X, Y, R³And R⁴With definition as described in the present invention.

In some embodiments, X H, C_1-12Alkyl, C_3-12Naphthenic base, C_6-12Aryl, 3-12 former molecular heterocycle Base or 5-12 former molecular heteroaryl, wherein each C_1-12Alkyl, C_3-12Naphthenic base, C_6-12Aryl, 3-12 atom The former molecular heteroaryl of the heterocycle of composition and 5-12 is individually optionally by 1,2,3,4 or 5 R¹Replaced group；

R¹For H, F, Cl, Br, CN, NO₂, oxo (=O) ,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b,-OC (= O)NR^aR^b,-OC (=O) OR^a,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-S (=O)₂R^a,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4It is sub- Alkyl, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (=O) O-C_1-4Alkylene Base, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN- C_1-4Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 3-12 atom group At heterocycle, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 The molecular heteroaryl of a original or (5-10 former molecular heteroaryl)-C_1-4Alkylidene, wherein each C_1-6Alkyl, C_2-6 Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 3-12 former molecular heterocycle, (3-12 atom The heterocycle of composition)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl)-C_1-4Alkylidene is independently unsubstituted or replaced 1,2,3 or 4 substituent group, institute Substituent group is stated independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；

Y is monocycle or bicyclic system comprising at least one N atom, and the monocycle is armaticity, and described bicyclic At least one ring is armaticity in system, wherein the Y is optionally by 1,2,3,4 or 5 R²Replaced group；

R²For H, F, Cl, Br, CN, NO₂, oxo (=O) ,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b,-OC (= O)NR^aR^b,-OC (=O) OR^a,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-S (=O)₂R^a,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4It is sub- Alkyl, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (=O) O-C_1-4Alkylene Base, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN- C_1-4Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, (3-12 atom group At heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, the molecular heteroaryl of 5 originals or (5-10 Former molecular heteroaryl)-C_1-4Alkylidene, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8 Naphthenic base-C_1-4Alkylidene, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylene Base, 5 molecular heteroaryls of original and (5-10 former molecular heteroaryl)-C_1-4Alkylidene it is independently unsubstituted or by Replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO- C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；

When Y is 4- quinazolinone, R²It is not phenyl；

Each R³And R⁴It independently is H, F, CN ,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b, R^bR^aNC (=O)-C_1-4 Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (=O) O-C_1-4Alkylene Base, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^bS (=O)₂N(R^c)-C_1-4Alkylidene, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4Alkylene Base, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 3-12 former molecular heterocycle Base, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 atom group At heteroaryl or (5-10 former molecular heteroaryl)-C_1-4Alkylidene, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6 Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 3-12 former molecular heterocycle, (3-12 former molecular miscellaneous Ring group)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 original Molecular heteroaryl)-C_1-4Alkylidene is independently unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group Independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；Or R³, R⁴With Together with the carbon atom being connected with them, the former molecular carbocyclic ring of substituted or non-substituted 3-8 or heterocycle are formed；With

Each R^a, R^bAnd R^cIt independently is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-4It is sub- Alkyl, 3-12 former molecular heterocycle, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Virtue Base-C_1-4Alkylidene, 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C_1-4Alkylidene, wherein Each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-4Alkylidene, 3-12 former molecular Heterocycle, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former Molecular heteroaryl and (5-10 former molecular heteroaryl)-C_1-4Alkylidene is independently unsubstituted or by 1,2,3 or 4 Replaced a substituent group, the substituent group is independently selected from F, Cl, CN, N₃, OH, NH₂, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkane Oxygroup or C_1-6Alkyl amino；Or R^a, R^bTogether with the nitrogen-atoms being connected with them, it is former to form substituted or non-substituted 3-8 Molecular heterocycle.

In other embodiment, X C_1-6Alkyl, C_3-8Naphthenic base, C_6-10Aryl, 3-7 former molecular heterocycle Base or 5-10 former molecular heteroaryl, wherein each C_1-6Alkyl, C_3-8Naphthenic base, C_6-10Aryl, 3-7 atom group At heterocycle and 5-10 former molecular heteroaryl individually optionally by 1,2,3 or 4 R¹Replaced group.

In other embodiment, R¹For H, F, Cl, CN, oxo (=O) ,-C (=O) OR^a,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4 Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 4-7 former molecular Heterocycle, (4-7 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former Molecular heteroaryl or (5-10 former molecular heteroaryl)-C_1-4Alkylidene, wherein each C_1-6Alkyl, C_2-6Alkene Base, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 4-7 former molecular heterocycle, (4-7 atom composition Heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 A molecular heteroaryl of original)-C_1-4Alkylidene is independently unsubstituted or replaced 1,2,3 or 4 substituent group, described to take Dai Ji is independently selected from F, Cl, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene.

In other embodiment, Y is the bicyclic system comprising at least one N atom, and in the bicyclic system At least one ring is armaticity, wherein the Y is optionally by 1,2,3 or 4 R²Replaced group；When Y is 4- quinazoline When ketone, R²It is not phenyl.

In other embodiment, R²For H, F, Cl, CN, oxo (=O) ,-C (=O) OR^a,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4 Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, (4-7 former molecular Heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, the molecular heteroaryl of 5 originals or (5-10 atom The heteroaryl of composition)-C_1-4Alkylidene, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Cycloalkanes Base-C_1-4Alkylidene, (4-7 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5 Former molecular heteroaryl and (5-10 former molecular heteroaryl)-C_1-4Alkylidene it is independently unsubstituted or by 1,2,3 or Replaced 4 substituent groups, the substituent group is independently selected from F, Cl, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene.

In other embodiment, each R³And R⁴It independently is H, F, CN ,-C (=O) NR^aR^b, R^bR^aNC (=O)-C_1-2 Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-2Alkylidene, R^aOC (=O) N (R^c)-C_1-2Alkylidene, R^bR^aNC (=O) O-C_1-2Alkylene Base, R^bR^aNS (=O)₂-C_1-2Alkylidene, R^bS (=O)₂N(R^c)-C_1-2Alkylidene, R^aO-C_1-2Alkylidene, R^bR^aN-C_1-2Alkylene Base, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-2Alkylidene, 4-7 former molecular heterocycle Base, (4-7 former molecular heterocycle)-C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, 5 molecular heteroaryls of original Or (5 molecular heteroaryls of original)-C_1-2Alkylidene, wherein each C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkanes Base, C_3-6Naphthenic base-C_1-2Alkylidene, 4-7 former molecular heterocycle, (4-7 former molecular heterocycle)-C_1-2Alkylene Base, phenyl, phenyl-C_1-2Alkylidene, 5 molecular heteroaryls of original and (5 molecular heteroaryls of original)-C_1-2Alkylidene is only On the spot unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；Or R³, R⁴Together with the carbon atom being connected with them, shape At substituted or non-substituted 3-8 former molecular carbocyclic ring or heterocycle.

In other embodiment, each R^a, R^bAnd R^cIt independently is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Ring Alkyl, C_3-6Naphthenic base-C_1-4Alkylidene, 4-7 former molecular heterocycle, 4-7 former molecular heterocycle-C_1-4Alkylene Base or 5-10 former molecular heteroaryl, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_3-6Ring Alkyl-C_1-4Alkylidene, 4-7 former molecular heterocycle, (4-7 former molecular heterocycle)-C_1-4Alkylidene and 5-10 A molecular heteroaryl of original is independently unsubstituted or replaced 1,2,3 or 4 substituent group, and the substituent group independently selects From F, CN, N₃, OH, NH₂, C_1-3Alkyl, C_1-3Halogenated alkyl, C_1-4Alkoxy or C_1-4Alkyl amino；Or R^a, R^bWith with their phases With nitrogen-atoms together with, form substituted or non-substituted 3-6 former molecular heterocycle.

In other embodiment, X C_1-4Alkyl, C_3-6Naphthenic base, phenyl, 3-6 former molecular heterocycle or 5-6 former molecular heteroaryl, wherein each C_1-4Alkyl, C_3-6Naphthenic base, phenyl, 3-6 former molecular heterocycle With 5-6 former molecular heteroaryl it is individually optional by 1,2,3 or 4 R¹Replaced group.

In other embodiment, R¹For H, F, Cl, CN, oxo (=O) ,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-N (R^c) S (=O)₂R^a, R^bR^aNC (=O)-C_1-2Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-2Alkylidene, R^bR^aNS (=O)₂-C_1-2Alkylidene, OR^a, NR^aR^b, R^aO-C_1-2Alkylidene, R^bR^aN-C_1-2It is sub- Alkyl, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-2Alkylidene, 4-6 former molecular miscellaneous Ring group, (4-6 former molecular heterocycle)-C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, 5-6 former molecular miscellaneous Aryl or (5-6 former molecular heteroaryl)-C_1-2Alkylidene, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-2Alkylidene, 4-6 former molecular heterocycle, (4-6 former molecular heterocycle)- C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, 5-6 former molecular heteroaryl and (the 5-6 molecular heteroaryl of original)- C_1-2Alkylidene is independently unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from F, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-2Alkylidene or R^bR^aN-C_1-2Alkylidene.

In other embodiment, Y is

Wherein, W independently is N or CH, and the Y is optionally by 1,2,3 or 4 R²Replaced group；When W is N, R²It is not phenyl.

In other embodiment, R²For H, F, Cl, CN, oxo (=O) ,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-N (R^c) S (=O)₂R^a, R^bR^aNC (=O)-C_1-2Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-2Alkylidene, R^bR^aNS (=O)₂-C_1-2Alkylidene, OR^a, NR^aR^b, R^aO-C_1-2Alkylidene, R^bR^aN-C_1-2It is sub- Alkyl, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-2Alkylidene, (4-6 former molecular miscellaneous Ring group)-C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, the molecular heteroaryl of 5 originals or (5-6 former molecular heteroaryl Base)-C_1-2Alkylidene, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-2Alkylene Base, (4-6 former molecular heterocycle)-C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, 5 molecular heteroaryls of original (5-6 former molecular heteroaryl)-C_1-2Alkylidene is independently unsubstituted or replaced 1,2,3 or 4 substituent group, The substituent group is independently selected from F, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-2Alkylidene or R^bR^aN-C_1-2Alkylidene.

In other embodiment, each R³And R⁴It independently is H, F, CN, C_1-3Alkyl, C_3-6Naphthenic base, 4-6 atom The heterocycle of composition or (4-6 former molecular heterocycle)-C_1-2Alkylidene, wherein each C_1-3Alkyl, C_3-6Naphthenic base, 4-6 former molecular heterocycle and (4-6 former molecular heterocycle)-C_1-2Alkylidene is independently unsubstituted or by 1, Replaced 2,3 or 4 substituent groups, the substituent group is independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-2 Alkylidene or R^bR^aN-C_1-2Alkylidene；Or R³, R⁴Together with the carbon atom being connected with them, substituted or non-substituted 3- is formed The molecular carbocyclic ring of 6 originals or heterocycle.

In other embodiment, each R^a, R^bAnd R^cIt independently is H, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Ring Alkyl, C_3-6Naphthenic base-C_1-2Alkylidene, 4-6 former molecular heterocycle, (4-6 former molecular heterocycle)-C_1-2It is sub- Alkyl or 5-6 former molecular heteroaryl, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6 Naphthenic base-C_1-2Alkylidene, 4-6 former molecular heterocycle, (4-6 former molecular heterocycle)-C_1-2Alkylidene and 5-6 A molecular heteroaryl of original is independently unsubstituted or replaced 1,2,3 or 4 substituent group, and the substituent group independently selects From F, CN, N₃, OH, NH₂, C_1-3Alkyl, C_1-3Halogenated alkyl, C_1-3Alkoxy or C_1-3Alkyl amino；Or R^a, R^bWith with their phases With nitrogen-atoms together with, form substituted or non-substituted 5-6 former molecular heterocycle.

In other embodiment, Y is

Wherein, W CH, and the Y is optionally by 1,2 or 3 R²Replaced group.

In other embodiment, Y is

Wherein, W N, and the Y is optionally by 1,2 or 3 R²Replaced group.

On the one hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention, pharmacy Upper acceptable salt and one or more pharmaceutically acceptable carriers, excipient, diluent, adjuvant, medium or they Combination.In some embodiments, pharmaceutical composition provided by the invention can further include one or more therapeutic agents.? Other embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray-type.

On the other hand, compound of the present invention can be used, pharmaceutically acceptable salt or its pharmaceutical composition are used In protection, processing, treatment or the purposes for mitigating the disease that the unsuitable PI3- kinase activity of patient mediates.

In some embodiments, PI3- kinases of the present invention is PI3K δ kinases.

In other embodiment, the disease that unsuitable PI3- kinase activity of the present invention mediates is respiratory tract Disease, virus infection, non-viral respiratory tract infection, anaphylactia, autoimmune disease, inflammatory disease, cardiovascular disease, Malignant hematologic disease, neurodegenerative disease, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, sperm motility are moved Plant repulsion, graft rejection, injury of lungs and pain.

In other embodiment, the disease that unsuitable PI3- kinase activity of the present invention mediates is asthma, Chronic obstructive pulmonary disease (COPD), viral respiratory infection, viral respiratory disease deteriorate, aspergillosis, leishmaniasis, mistake Quick property rhinitis, allergic dermatitis, rheumatic arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis are disliked Property blood disease, neurodegenerative disease, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, sperm motility, transplanting Repel, graft rejection, injury of lungs, pain relevant to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain Bitterly, neuralgia after liver, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain.

On the other hand, the present invention is provided to the method for -3 kinases of inhibition of phosphatidylinositol3 (PI3- kinases), this method packets It includes: contacting PI3- kinases with a effective amount of compound disclosed in this invention；In some embodiments, contact procedure can be into One step includes the cell of contact expression PI3- kinases；In the other embodiment of this method, inhibiting effect generation is being endured In the object of one or more type PI3- kinases obstacle related diseases.One or more type PI3- according to the present invention swash The relevant disease of enzyme obstacle includes autoimmune disease, rheumatic arthritis, respiratory disease, allergic reaction and various The cancer of type.

In some embodiments, method of the present invention includes applying second therapeutic agent to study subject.

In other embodiments, PI3- kinase mediated disease is selected from rheumatic arthritis, ankylosing spondylitis, and bone closes Section is scorching, psoriatic arthritis, psoriasis, diseases associated with inflammation and autoimmune disease；Other embodiments, PI3- kinases are situated between The disease led is selected from cardiovascular disease, atherosclerosis, hypertension, Deep vain thrombosis, apoplexy, myocardial infarction, shakiness Centering colic pain, thromboembolism, pulmonary embolism, thrombolysis disease, Acute arterial ischeamia, peripheral thrombus obstruction and coronary artery disease.Separately Some embodiments, PI3- kinase mediated disease are selected from cancer, colon cancer, glioblastoma, carcinoma of endometrium, liver cancer, lung Cancer, melanoma, kidney, thyroid cancer, lymthoma, lymphoproliferative disorder, Small Cell Lung Cancer, prognosis of squamous cell lung cancer, colloid Tumor, breast cancer, prostate cancer, oophoroma, cervical carcinoma and leukaemia.In other embodiments, PI3- kinase mediated disease Selected from type-2 diabetes mellitus；In other embodiments, PI3- kinase mediated disease is selected from respiratory disease, and bronchitis is roared Asthma and chronic obstructive pulmonary disease；In other embodiments, study subject is people.

On the other hand, the present invention relates to the treatment method of PI3- kinase mediated disease, the treatment method includes using this The step of invention compound or pharmaceutical composition are administered.

On the other hand, the present invention relates to rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, The treatment of psoriasis, diseases associated with inflammation or autoimmune disease, the treatment include using the compounds of this invention or medicine group Close the step of object is administered.

On the other hand, the present invention relates to include asthma, Chronic Obstructive Pulmonary Disease (COPD) and idiopathic pulmonary fibrosis (IPF) etc. the treatment of respiratory diseases, the treatment includes the step being administered using the compounds of this invention or pharmaceutical composition Suddenly.

On the other hand, the present invention relates to inflammatory bowel disease, inflammatory ocular disease, inflammation or unstable bladder disease, The skin disease of inflammatory component, chronic inflammation, systemic loupus erythematosus (SLE), myasthenia gravis, acute diseminated encephalomyelitis, Idiopathic blood platelet reduction property purpura, multiple sclerosis, Sjogren syndrome and autoimmune hemolytic anemia, mistake The treatment of quick property and pleoergy disease, the treatment includes the step being administered using the compounds of this invention or pharmaceutical composition Suddenly.

On the other hand, involved in the present invention to be mediated by PI3K activity, it is active or relevant to PI3K activity dependent on PI3K The treatment of cancer, the especially activity of PI3K δ, the treatment include the administration of the compound of any of above and following embodiment Step.

On the other hand, the present invention relates to the treatment methods for being selected from following cancer: acute myelogenous leukemia, spinal cord development are different Normal syndrome, myeloproliferative disease, chronic myelogenous leukemia, T cell acute lymphoblastic leukemia, B cell acute lymphoblastic are thin Born of the same parents' leukaemia, non-Hodgkin lymphoma, B cell lymphoma, solid tumor and breast cancer, the treatment method include using the present invention The step of compound or pharmaceutical composition are administered.

On the other hand, the present invention relates to the compounds of this invention as the application in terms of drug.

On the other hand, the answering in terms of the disease mediated drug of preparation treatment PI3K the present invention relates to the compounds of this invention With.

On the other hand, the present invention relates to the compounds of this invention preparation treat rheumatoid arthritis, ankylosing spondylitis, Osteoarthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation, including asthma, Chronic Obstructive Pulmonary Disease (COPD) He Tefa Property pulmonary fibrosis (IPF) etc. respiratory diseases, the application of drug in terms of autoimmune disease and cancer.

Unless otherwise mentioned, the present invention includes the stereoisomer of all the compounds of this invention, and geometric isomer mutually makes a variation Structure body, solvate, hydrate, metabolite, salt and pharmaceutically acceptable prodrug.

In some embodiments, the salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to object Matter or composition must be with other ingredients comprising preparation and/or the mammal treated with it chemically and/or in toxicology It is compatible.

The compound of the present invention further includes the form of its salt, which is not necessarily pharmaceutically acceptable salt, but can be with It is used to prepare and/or purifies the intermediate of the compound of the present invention and/or the enantiomer for separating the compounds of this invention.

The compounds of this invention including its salt can also be obtained in the form of its hydrate, or including other for its crystallization Solvent.The compounds of this invention can form the solvate with acceptable solvent (including water) inherently or by design； Therefore, the invention also includes its solvated and unsolvated formies.

On the other hand, the present invention provides the preparation of compound shown in formula (I), the methods of separation and purifying.Of the present inventionization Closing object may the form comprising several asymmetric centers or its usually described raceme mixture.The present invention is also into one Step includes racemic mixture, partial racemic compound and isolated enantiomer and diastereomer.

The compounds of this invention can be with one in possible isomers, rotational isomer, atropisomer, tautomer The form of or mixtures thereof kind form exists, and the present invention can further include the isomers of the compounds of this invention, rotational isomeric Body, atropisomer, the mixture of tautomer or isomers, rotational isomer, atropisomer, tautomer Part mixes or the separated isomers opened, rotational isomer, atropisomer, tautomer.

On the other hand, compound of the present invention includes chemical combination defined in the present invention using various isotope labellings Object, for example, wherein there is radioactive isotope, such as³H,¹⁴C and¹⁸Those of F compound, or wherein there is the same position of on-radiation Element, such as²H and¹³The compound of C.

On the other hand, the method for preparation, separation and the purifying of the compound for being included the present invention relates to formula (I).

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.

Detailed description of the invention book

Definition and general terms

The present invention will list in detail document corresponding to the content determining materialization, and embodiment is all accompanied by structure The diagram of formula and chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, these may be as right Existing invention field is included in defined in it is required that like that.Those skilled in the art will identify it is many similar or equivalent to This described method and substance, these can be applied to the practice of the present invention.The present invention is limited to absolutely not method and substance Description.There are many documents and similar substance to distinguish or contradict with the present patent application including but not limited to term Definition, the usage of term, the technology of description, or the range controlled as the present patent application.

Unless otherwise noted, technical and scientific term used in the present invention and the technical field of the invention technical staff It is conventional understand have the same meaning, unless otherwise noted, disclose all patents public affairs cited in full content in the present invention It opens publication and is integrally incorporated the present invention by reference.

The present invention will be using defined below unless other aspects show.Purpose according to the present invention, chemical element is according to member Plain periodic table, CAS version and chemicals handbook, 75,^thEd, 1994 define.In addition, organic chemistry General Principle is shown in “Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999, and“March′s Advanced Organic Chemistry”,by Michael B.Smith and Jerry March, John Wiley&Sons, New York:2007, therefore all contents of the invention have all merged bibliography.

Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As also referring to primate (such as people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc..Certain In embodiment, the study subject is primate.In other other embodiments, the study subject is people.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations Scheme, " patient " refer to people.

The invention also includes the compounds of this invention of isotope labelling, except for the following fact with it is those of of the present invention Compound is identical: one or more atoms are different from the original of natural common atomic quality or mass number by atomic mass or mass number Filial generation is replaced.The Exemplary isotopes that can be also introduced into the compounds of this invention include the same position of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine Element, such as²H,³H,¹³C,¹⁴C,¹⁵N,¹⁶O,¹⁷O,³¹P,³²P,³⁶S,¹⁸F and³⁷Cl。

The compounds of this invention and the compound comprising other of aforementioned isotopes and/or other atoms isotope Pharmaceutically acceptable salt is included within the scope of the present invention.The compounds of this invention of isotope labelling, such as the same position of radioactivity Element, such as³H and¹⁴C, which is incorporated into the compounds of this invention, can be used for drug and/or substrate tissue distributional analysis.Due to it is easily prepared with And detection, tritium generation, that is,³H and carbon-14, i.e.,¹⁴C, isotope are particularly preferred.In addition, with the isotope of weight, such as deuterium, i.e.,²H Replace, it is possible to provide the advantage in some treatments from bigger metabolic stability, such as increased Half-life in vivo or reduction Volume requirements.It therefore, in some cases may be preferred.

The Stereochemical definitions and convention that the present invention uses are generally according to S.P.Parker, Ed, McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc.,New York,1994.The compounds of this invention can contain asymmetric center or chiral centre, therefore different with different solids Configuration formula exists.It is expected that all stereoisomeric forms in any ratio of the compounds of this invention, including but not limited to diastereo-isomerism Body, enantiomter and atropisomer (atropisomer) and their mixture such as racemic mixture are also contained in this Within invention scope.Many organic compounds exist with optical active forms, i.e., they, which have, sends out the plane of linearly polarized light The ability of raw rotation.When describing compound with optical activation, indicated using prefix D and L or R and S with regard in molecule The absolute configuration of molecule for chiral centre (or multiple chiral centers).Prefix d and l or (+) and (-) are for appointed compound The symbol of caused linearly polarized light rotation, wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is Dextrorotation.For given chemical structure, other than these stereoisomers each other mirror image, these stereoisomers are identical 's.Specific stereoisomer is alternatively referred to as enantiomter, and the mixture of the isomers is commonly referred to as enantiomerism The mixture of body.The 50:50 mixture of enantiomter is known as racemic mixture or racemic modification, when in chemical reaction or side When there is no stereoselectivity or stereospecificity in method, the racemic mixture or racemic modification may occur in which.

According to the selection of raw material and method, the compounds of this invention can be with one in possible isomers or they mixed The form for closing object exists, such as pure optical isomer, or as isomer mixture, such as different as racemic and non-corresponding Structure body mixture, this depends on the quantity of asymmetric carbon atom.Chiral synthesis can be used in (R)-or (S)-isomers of optical activity Son or chiral agents preparation, or split using routine techniques.If this compound contains a double bond, substituent group may be E or Z Configuration；If containing disubstituted naphthenic base in this compound, the substituent group of naphthenic base may for cis or trans (cis- or Trans-) configuration.

The compounds of this invention can contain asymmetric center or chiral centre, therefore be deposited with different stereoisomer forms ?.It is expected that all stereoisomer forms of the compounds of this invention, including but not limited to diastereoisomer, mapping Isomers and atropisomer (atropisomer) and geometry (or conformation) isomers and their mixture, as racemic is mixed Object is closed, is all within the scope of the present invention.

Unless otherwise noted, the structure that the present invention describes be also represented by including this structure all isomers (e.g., enantiomer, Diastereomer atropisomer (atropisomer) and geometry (or conformation)) form；For example, R the and S structure of each asymmetric center Type, (Z) and (E) double bond isomer, and (Z) and (E) conformer.Therefore, the single spatial chemistry of the compounds of this invention Isomers and mixture of enantiomers, non-enantiomer mixture and geometric isomer (or conformer) mixture are in this hair Within the scope of bright.

Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.

The shape that any asymmetric atom (for example, carbon etc.) of the compounds of this invention can be enriched with racemic or enantiomer Formula exists, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom is at (R)- Or there is at least 50% enantiomeric excess in terms of (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, until Few 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. If it would be possible, the substituent group on atom with unsaturated double-bond can be deposited in the form of cis--(Z)-or trans--(E)- ?.

Therefore, as described in the present invention, the compound of the present invention can be with possible isomers, rotational isomeric The form of or mixtures thereof one of body, atropisomer, tautomer form exists, for example, substantially pure geometry Or mixtures thereof (cis or trans) isomers, diastereoisomer, optical isomer (enantiomer), racemic modification form.

Resulting any isomer mixture can be separated into pure or substantially pure according to the physical chemical differences of component Geometry or optical isomer, diastereoisomer, racemic modification, such as separated by chromatography and/or fractional crystallization.

The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high pressure liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can prepare (e.g., Jacques, et al., Enantiomers, Racemates and by asymmetric syntheses Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen, S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed., Univ.of Notre Dame Press,Notre Dame,IN 1972)。

As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or non-substituted ".Term is " optionally Ground ", " optional " or " optional " refer to then described event or situation can with but may not occur, and the description is including wherein There is a situation where the event or situations, and wherein there is a situation where the event or situations.In general, term " optionally " Whether it is before the term " replaced ", all indicate one or more hydrogen atoms in given structure by specific substituent group institute Replace.Unless otherwise indicated, an optional substituent group can be replaced at various substitutable position of that group.When More than one position can be replaced one or more substituent groups selected from specific group, then replacing in given structural formula Base can replace at various locations identical or differently.Wherein the substituent group can be, but be not limited to, F, Cl, Br, CN, N₃, OH, NH₂, NO₂, oxo (=O) ,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b,-OC (=O) NR^aR^b,-OC (=O) OR^a,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-S (=O)₂R^a,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4Alkylidene, R^bR^aNC (= O)N(R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (=O) O-C_1-4Alkylidene, R^bR^aNS (=O)₂- C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4Alkylidene, C_1-12 Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkyl amino, C_2-6Alkenyl, C_2-6Alkynyl, C_3-12Naphthenic base, C_3-12Naphthenic base- C_1-4Alkylidene, 3-12 former molecular heterocycle, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-12Aryl, C_6-12Aryl-C_1-4Alkylidene, 5-12 former molecular heteroaryl or (5-12 former molecular heteroaryl)-C_1-4Alkylene Base, wherein the R^a, R^bAnd R^cWith definition as described herein.

In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.

It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C_1-6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

Terminology used in the present invention " alkyl " or " alkyl group " indicate saturated straight chain or branch containing 1-20 carbon atom Monovalence hydrocarbon atomic group.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom；Some of them are implemented Example is that alkyl group contains 1-12 carbon atom；Other embodiment is that alkyl group contains 1-10 carbon atom；In addition Some embodiments are that alkyl group contains 1-8 carbon atom；Other embodiment is that it is former that alkyl group contains 1-6 carbon Son；Other embodiment is that alkyl group contains 1-4 carbon atom；Other embodiment is that alkyl group contains 1-3 A carbon atom.

The example of alkyl group includes, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-propyl (n- Pr ,-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,- CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), tert-butyl (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), 2- amyl (- CH (CH₃)CH₂CH₂CH₃), 3- amyl (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 3- methyl-1-butyl (- CH₂CH₂CH(CH₃)₂), 2- first Base -1- butyl (- CH₂CH(CH₃)CH₂CH₃), n-hexyl (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- hexyl (- CH (CH₃) CH₂CH₂CH₂CH₃), 3- hexyl (- CH (CH₂CH₃)(CH₂CH₂CH₃)), 2- methyl -2- amyl (- C (CH₃)₂CH₂CH₂CH₃), 3- first Base -2- amyl (- CH (CH₃)CH(CH₃)CH₂CH₃), 4- methyl -2- amyl (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- penta Base (- C (CH₃)(CH₂CH₃)₂), 2- methyl -3- amyl (- CH (CH₂CH₃)CH(CH₃)₂), 2,3- dimethyl -2- butyl (- C (CH₃)₂CH(CH₃)₂), 3,3- dimethyl -2- butyl (- CH (CH₃)C(CH₃)₃), n-heptyl, n-octyl, etc., wherein described Alkyl group can be independently unsubstituted or replaced one or more substituent group described in the invention.

Term " alkyl " used in the present invention and its prefix " alkane " all include the saturated carbon chains of straight chain and branch.

Two obtained saturations of hydrogen atom are removed in term " alkylidene " expression from linear or branched saturated hydrocarbon base Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, and other embodiment is, sub- Alkyl group contains 1-6 carbon atom, and other embodiment is that alkylidene group contains 1-4 carbon atom, and other is real Applying example is, alkylidene group contains 1-2 carbon atom.Such example includes methylene (- CH₂), ethylidene (- CH₂CH₂), Isopropylidene (- CH (CH₃)CH₂) etc., wherein the alkylidene group can be independently unsubstituted or one or more Replaced substituent group described in the invention.

Term " alkenyl " indicates former containing 2-12 carbon atom or 2-8 carbon atom or 2-6 carbon atom or 2-4 carbon The monovalent hydrocarbon of the linear chain or branched chain of son, wherein at least one position are undersaturated condition, i.e., a C-C is sp²Double bond, wherein Alkenyl group can be independently unsubstituted or replaced one or more substituent group described in the invention, including group has The positioning of " suitable " negation or " E " " Z ", wherein specific example includes, but is not limited to, vinyl (- CH=CH₂), allyl (-CH₂CH=CH₂) etc..

Term " alkynyl " indicates 2-12 carbon atom or 2-8 carbon atom or 2-6 carbon atom or 2-4 carbon atom Linear chain or branched chain monovalent hydrocarbon, wherein at least one position is undersaturated condition, i.e. C-C is tri- key of sp, wherein alkynes Base group can be independently unsubstituted or replaced one or more substituent group described in the invention, specific example packet It includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH₂C ≡ CH), 1- propinyl (- C ≡ C-CH₃) etc..

Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-20 carbon atom, some of real Applying example is, alkoxy base contains 1-10 carbon atom, and other embodiment is that alkoxy base contains 1-8 carbon atom, Other embodiment is that alkoxy base contains 1-6 carbon atom, and other embodiment is that alkoxy base contains 1-4 A carbon atom, other embodiment are that alkoxy base contains 1-3 carbon atom.

The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO ,- OCH₂CH₃), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH₂CH₂CH₃), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH₃)₂), 1- butoxy (n-BuO, n- butoxy ,-OCH₂CH₂CH₂CH₃), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH₂CH(CH₃)₂), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH₃)CH₂CH₃), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH₃)₃), 1- amoxy (n- amoxy ,-OCH₂CH₂CH₂CH₂CH₃), 2- amoxy (- OCH (CH₃) CH₂CH₂CH₃), 3- amoxy (- OCH (CH₂CH₃)₂), 2- methyl -2- butoxy (- OC (CH₃)₂CH₂CH₃), 3- methyl -2- fourth Oxygroup (- OCH (CH₃)CH(CH₃)₂), 3- methyl-l- butoxy (- OCH₂CH₂CH(CH₃)₂), 2- methyl-l- butoxy (- OCH₂CH(CH₃)CH₂CH₃), etc., wherein the alkoxy base can be independently unsubstituted or by this one or more hair Replaced bright described substituent group.

Term " halogenated alkyl ", " halogenated alkenyl " or " halogenated alkoxy " indicate alkyl, and alkenyl or alkoxy base are by one Replaced a or multiple halogen atoms, such example includes, but is not limited to, trifluoromethyl, trifluoromethoxy etc..

Term " carbocyclic ring ", " carbocylic radical " or " annular aliphatic " refer to have one or more tie points be connected to molecule its Remaining part point, non-aromatic, saturation or part are unsaturated, include 3-12 carbon atom or 3-10 carbon atom or 3-8 The monocycle of carbon atom or 3-6 carbon atom, bicyclic and three-ring system.Its bicyclic system includes that spiral shell is bicyclic and condensed-bicyclic.Properly Carbocylic radical group include, but is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.The example of carbocylic radical group further comprises, But it is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkene Base, cyclohexyl, 1- cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, suberyl, Cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..

Term " naphthenic base " refers to the rest part for having one or more tie points to be connected to molecule, saturation, contains 3-12 The monocycle of a carbon atom, bicyclic or three-ring system.Its bicyclic system includes that spiral shell is bicyclic and condensed-bicyclic.Some of embodiments, Naphthenic base is the ring system containing 3-10 carbon atom；Other embodiment, naphthenic base are the ring systems containing 3-8 carbon atom； Other embodiment, naphthenic base are the ring systems containing 3-6 carbon atom；Other embodiment, naphthenic base are containing 5-6 carbon The ring system of atom；And the group of naphthene base can be independently unsubstituted or described in the invention be taken by one or more Replaced Dai Ji.

Term " naphthenic base alkylidene " indicates that alkyl group can be replaced one or more groups of naphthene base, wherein alkane Base and group of naphthene base have meaning as described in the present invention.Some of embodiments are, naphthenic base alkylidene group refer to " compared with Rudimentary naphthenic base alkylidene " group, i.e. group of naphthene base are connected to C_1-6Alkyl group on.Other embodiment is ring Alkyl group is connected to C_1-4Alkyl group on.Other embodiment is that group of naphthene base is connected to C_1-3Alkyl group On.Other embodiment is that group of naphthene base is connected to C_1-2Alkyl group on.Such example includes, but and unlimited In, cyclopropylethyl, cyclopentyl-methyl, cyclohexyl methyl etc..The naphthenic base alkylidene group can not taken independently Generation or replaced one or more substituent groups described in the invention.

Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to the saturation comprising 3-12 annular atom or portion Dividing unsaturated, nonaromatic monocyclic, bicyclic or tricyclic system, wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom, And this ring system has one or more tie points to be connected with the rest part of molecule.Unless otherwise stated, heterocycle can be carbon Base or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.The sulphur atom of ring can optionally be oxidized to S- oxygen Compound.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.The example of heterocycle includes, but are not limited to: epoxy second Alkyl, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazoline Base, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1, 3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, Piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane base, high piperazine base, homopiperidinyl, Oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulphur azepineBase, indoline base, 1,2,3,4- tetra- Hydrogen isoquinoline base, 1,3- benzo two dislike cyclopentadienyl, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base.- CH in heterocycle₂Group 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidones are included, but are not limited to by-C (=O)-example replaced Base, 3,5- dioxy piperazine piperidinyls, hybar X base.The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane Base and 1,1- dioxothiomorpholinyl.The heterocyclyl groups can be optionally by one or more described in the invention Replaced substituent group.

In some embodiments, heterocycle is the 3-8 molecular heterocycle of original, is referred to comprising 3-8 annular atom Saturation or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 3-8 Former molecular heterocycle can be carbon-based or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.The sulphur of ring is former Son can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.3-8 atom The example of the heterocycle of composition includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, Pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran Base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro Pyranose, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes Base, dithianyl, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, DiazaBase, sulphur azepineBase.- CH in heterocycle₂Group includes, but are not limited to 2- oxygen by-C (=the O)-example replaced For pyrrolidinyl, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyls and hybar X base.In heterocycle The example that sulphur atom is oxidized includes, but are not limited to sulfolane base, 1,1- dioxothiomorpholinyl.The 3-8 atom The heterocyclyl groups of composition can be optionally replaced one or more substituent groups described in the invention.

In some embodiments, heterocycle is the 3-7 molecular heterocycle of original, is referred to comprising 3-7 annular atom Saturation or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 3-7 Former molecular heterocycle can be carbon-based or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.The sulphur of ring is former Son can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.3-7 atom The example of the heterocycle of composition includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, Pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran Base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro Pyranose, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes Base, dithianyl, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, DiazaBase, sulphur azepineBase.- CH in heterocycle₂Group includes, but are not limited to 2- oxygen by-C (=the O)-example replaced For pyrrolidinyl, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyls and hybar X base.In heterocycle The example that sulphur atom is oxidized includes, but are not limited to sulfolane base, 1,1- dioxothiomorpholinyl.The 3-7 atom The heterocyclyl groups of composition can be optionally replaced one or more substituent groups described in the invention.

In some embodiments, heterocycle is the 3-6 molecular heterocycle of original, is referred to comprising 3-6 annular atom Saturation or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 3-6 Former molecular heterocycle can be carbon-based or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.The sulphur of ring is former Son can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.3-6 atom The example of the heterocycle of composition includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, Pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran Base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro Pyranose, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes Base, dithianyl, thiophene oxane base.- CH in heterocycle₂Group includes, but are not limited to 2- oxygen by-C (=the O)-example replaced For pyrrolidinyl, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyls and hybar X base.In heterocycle The example that sulphur atom is oxidized includes, but are not limited to sulfolane base and 1,1- dioxothiomorpholinyl.Described 3-6 is former Molecular heterocyclyl groups can be optionally replaced one or more substituent groups described in the invention.

In some embodiments, heterocycle is the 4-7 molecular heterocycle of original, is referred to comprising 4-7 annular atom Saturation or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 4-7 Former molecular heterocycle can be carbon-based or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.The sulphur of ring is former Son can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.4-7 atom The example of the heterocycle of composition includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- Pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran Base, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- Pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithiane Base, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diaza Base, sulphur azepineBase.- CH in heterocycle₂Group includes, but are not limited to 2- oxo-pyrrolidine by-C (=the O)-example replaced Base, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyls and hybar X base.Sulphur atom quilt in heterocycle The example of oxidation includes, but are not limited to sulfolane base, 1,1- dioxothiomorpholinyl.Described 4-7 is former molecular miscellaneous Cyclic groups can be optionally replaced one or more substituent groups described in the invention.

In some embodiments, heterocycle is the 4-6 molecular heterocycle of original, is referred to comprising 4-6 annular atom Saturation or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 4-6 Former molecular heterocycle can be carbon-based or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.The sulphur of ring is former Son can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.4-6 atom The example of the heterocycle of composition includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- Pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran Base, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- Pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithiane Base, thiophene oxane base.- CH in heterocycle₂Group includes, but are not limited to 2- oxo-pyrrolidine by-C (=the O)-example replaced Base, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyls and hybar X base.Sulphur atom quilt in heterocycle The example of oxidation includes, but are not limited to sulfolane base and 1,1- dioxothiomorpholinyl.Described 4-6 is former molecular Heterocyclyl groups can be optionally replaced one or more substituent groups described in the invention.

In some embodiments, heterocycle is the 5-6 molecular heterocycle of original, is referred to comprising 5-6 annular atom Saturation or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 5-6 Former molecular heterocycle can be carbon-based or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.The sulphur of ring is former Son can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.5-6 atom The example of the heterocycle of composition includes, but are not limited to: pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazoles Alkyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy ring Amyl, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, Morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane base.- CH in heterocycle₂Group quilt-C (= O)-example for replacing includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base, and 3,5- bis- Oxo-piperidine base and hybar X base.The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base and 1,1- Dioxothiomorpholinyl.The former molecular heterocyclyl groups of described 5-6 can be optionally by one or more present invention Replaced described substituent group.

In other embodiments, heterocycle is 6 molecular heterocycles of original, is referred to full comprising 6 annular atoms And/or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 6 atoms The heterocycle of composition can be carbon-based or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.The sulphur atom of ring can To be optionally oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.6 originals are molecular The example of heterocycle includes, but are not limited to: THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydric thiapyran Base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane base.- CH in heterocycle₂Base Group includes, but are not limited to 2- piperidone base, 3,5- dioxy piperazine piperidinyls and hybar X base by-C (=the O)-example replaced. The example that sulphur atom is oxidized in heterocycle includes, but are not limited to 1,1- dioxothiomorpholinyl.6 atom groups At heterocyclyl groups can be optionally replaced one or more substituent groups described in the invention.

In other embodiments, heterocycle is 5 molecular heterocycles of original, is referred to full comprising 5 annular atoms And/or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 5 atoms The heterocycle of composition can be carbon-based or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.The sulphur atom of ring can To be optionally oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.5 originals are molecular The example of heterocycle includes, but are not limited to: pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, miaow Oxazoline base, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two Sulphur cyclopenta.- CH in heterocycle₂Group includes, but are not limited to 2- oxo-pyrrolidine base, oxygen by-C (=the O)-example replaced Generation -1,3- thiazolidinyl.The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base.5 originals Molecular heterocyclyl groups can be optionally replaced one or more substituent groups described in the invention.

Term " heterocycloalkylene " indicates that alkyl group can be replaced one or more heterocyclyl groups, wherein alkane Base and heterocyclyl groups have meaning as described in the present invention.Some of embodiments are, heterocycloalkylene group refer to " compared with Rudimentary heterocycloalkylene " group, i.e. heterocyclyl groups are connected to C_1-6Alkyl group on.Other embodiment is, miscellaneous Cyclic groups are connected to C_1-4Alkyl group on.Other embodiment is that heterocyclyl groups are connected to C_1-2Alkyl group On.Such example includes, but is not limited to, 2- pyrrolidines ethyl, 3- azetidine methyl etc..The heterocycle alkylene Base group can be independently unsubstituted or replaced one or more substituent group described in the invention.

Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original, and 1,2,3,4- tetralyl It is 10 molecular groups of naphthene base of original.

Term " hetero atom " refers to O, S, N, P and Si, including N, the form of any oxidation state of S or P；Any basic nitrogen Quaternary ammonium form；Or substitutive nitrogen in heterocycle, for example, N (as the N in 3,4- dihydro-2 h-pyrrole base), NH is (as pyrrolidines NH in base) or NR (NR in pyrrolidinyl replaced as N-).

Term " halogen " refers to F, Cl, Br or I.

Term " N₃" indicate a nitrine structure.This group can be connected with other groups, for example, can be with a first Base is connected to form triazonmethane (MeN₃), or phenylazide (PhN is connected to form with a phenyl₃)。

Term " aryl " can be used alone or as " aralkyl ", a big portion of " aralkoxy " or " aryloxy alkyl " Point, indicate the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, bicyclic and tricyclic carbocyclic ring System, wherein at least one ring system be it is aromatic, wherein each ring system includes the 3-7 molecular ring of original, and is had One or more attachment points are connected with the rest part of molecule.Term " aryl " can be used interchangeably with term " aromatic rings ", such as Aromatic rings may include phenyl, naphthalene and anthryl.The aryl group can be independently unsubstituted or by one or more sheet It invents replaced described substituent group.

Term " aryl alkylene " indicate alkyl group can replaced one or more aryl groups, wherein alkyl and Aryl group has meaning as described in the present invention, and some of embodiments are that arylalkylene groups refer to the " virtue of lower level Base alkylidene " group, i.e. aryl group are connected to C_1-6Alkyl group on.Other embodiment is arylalkylene groups Refer to containing C_1-4Alkyl " benzeme alkylene ".Other embodiment is that arylalkylene groups refer to that aryl group is connected to C_1-2Alkyl group on.Wherein specific example includes benzyl, diphenyl methyl, phenethyl etc..The arylalkylene groups It can be independently unsubstituted or replaced one or more substituent groups described in the invention.

Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Indicate the monocycle containing 5-14 annular atom or 5-12 annular atom or 5-10 annular atom or 5-6 annular atom, it is bicyclic, And three-ring system, wherein at least one ring system are aromatic, and at least one ring system includes one or more hetero atoms, Wherein each ring system includes 5-7 former molecular ring, and has one or more attachment points to be connected with molecule rest part. Term " heteroaryl " can be used interchangeably with term " hetero-aromatic ring " or " heteroaromatics ".In some embodiments, heteroaryl Base is the heteroatomic 5-12 former molecular heteroaryl that O, S and N are independently selected from comprising 1,2,3 or 4.In other implementations In scheme, heteroaryl is the heteroatomic 5-10 former molecular heteroaryl that O, S and N are independently selected from comprising 1,2,3 or 4. In other embodiments, heteroaryl is the heteroatomic 5-6 atom group that O, S and N are independently selected from comprising 1,2,3 or 4 At heteroaryl.In other embodiments, heteroaryl is to be independently selected from heteroatomic the 5 of O, S and N comprising 1,2,3 or 4 A molecular heteroaryl of original.

Other embodiment is that heteroaryl includes monocyclic groups below, but is not limited to these monocyclic groups: 2- furan It mutters base, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- is different Oxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl group, 3- pyridine Base, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazolyl (such as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrrole Oxazolyl (e.g., 2- pyrazolyl and 3- pyrazolyl), isothiazolyl, 1,2,3-oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- dislikes two Oxazolyl, 1,3,4- oxadiazoles base, 1,2,3-triazoles base, 1,2,4- triazolyl, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole Base, 1,2,5- thio biphosphole base, pyrazinyl, 1,3,5-triazines base；It also include bicyclic radicals below, but it is double to be not limited to these Cyclic group: benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- Quinolyl, 3- quinolyl, 4- quinolyl) and isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl).Institute Heteroaryl groups are stated optionally replaced one or more substituent groups described in the invention.

Term " heteroarylalkylenyl " indicates that alkyl group can be replaced one or more heteroaryl groups, wherein alkane Base and heteroaryl groups have meaning as described in the present invention, and some of embodiments are, heteroarylalkylenyl group refer to " compared with Rudimentary heteroarylalkylenyl " group, i.e. heteroaryl groups are connected to C_1-6Alkyl group on.Other embodiment is, miscellaneous Aryl group is connected to C_1-4Alkyl group on.Other embodiment is that heteroaryl groups are connected to C_1-2Alkyl group On.Wherein specific example includes 2- picolyl, 3- furylethyl etc..The heteroarylalkylenyl group can independently not It is substituted or replaced one or more substituent groups described in the invention.

No matter term " carboxyl " is single use or is used in conjunction with other terms, such as " carboxyalkyl ", expression-CO₂H。

No matter term " carbonyl " is single use or is used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", table Show-(C=O)-.

Term " alkyl amino " includes " N- alkyl amino " and " N, N- dialkyl amido ", and wherein amino group is independently Ground is replaced one or two alkyl group.Some of embodiments are that alkyl amino is one or two C_1-6Alkyl connection The alkylamino group of lower level on to nitrogen-atoms.Other embodiment is that alkyl amino is C_1-3Lower level alkyl Amino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but not It is limited to, N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- diethylamino etc..

Term " arylamino " indicates amino group replaced one or two aryl group, and such example includes, But it is not limited to N- phenyl amino.Some of embodiments are that the aromatic ring on arylamino can be further substituted.

Term " aminoalkyl " indicates the C replaced one or more amino_1-10Linear or branched alkyl group group.Wherein Some embodiments are that aminoalkyl is the C replaced one or more amino groups_1-6" aminoalkyl of lower level ", in this way Example include, but is not limited to, amino methyl, amino-ethyl, aminopropyl, aminobutyl and Aminohexyl.

As described in the invention, substituent group draw one be keyed to formed on the ring at center ring system (such as structure a and Shown in structure b-1, b-2 and b-3) it represents substituent group any substitutive position on ring and can replace.For example, structure a generation Any possible substituted position on table B ring, as shown in structure b-1, b-2 and b-3:

Contain one or more degrees of unsaturation in " unsaturated " the expression group of term as used in the present invention.

Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.

Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.It is completely begged for about pro-drug By following documents can be referred to: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C_1-8Sulphonic acid compound and aromatic sulphonic acid compound.

" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.

As described herein, term " pharmaceutically acceptable carrier " includes any solvent, decentralized medium, coating agents, Surfactant, antioxidant, preservative (such as antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizing agent, bonding Agent, excipient, dispersing agent, lubricant, sweetener, flavoring agent, colorant, or combinations thereof object, these carriers be all affiliated technology Known (such as Remington ' s Pharmaceutical Sciences, the 18th Ed.Mack of field technical staff Printing Company, 1990, p.1289-1329 described).In addition to any conventional carrier situation incompatible with active constituent Outside, cover its purposes in treatment or pharmaceutical composition.

" therapeutically effective amount " of term the compounds of this invention, which refers to, will cause the biology or medicinal response, example of study subject It such as reduces or inhibits enzyme or protein active or improve symptom, mitigate symptom, slow down or delay progression of disease or prevention disease The amount of used the compounds of this invention.It is applied in some non-limiting embodiments, term " therapeutically effective amount " refers to work as The used amount to the effective the compounds of this invention of the following terms when study subject: (1) it at least partly mitigates, inhibit, prevention And/or improve illness that (i) is mediated by PI3K or that (ii) and PI3K are active related or (iii) is characterized by PI3K activity or Conditions or diseases；Or (2) mitigate or inhibit PI3K activity.In other non-limiting embodiments, " treatment is effective for term Amount " refers to when being applied to cell or tissue or non-cellular biological material or medium, at least partly mitigates illness or inhibition The amount of the effective the compounds of this invention of PI3K；Or mitigates illness at least to a certain extent or inhibit the activity of PI3K.Term The content of " therapeutically effective amount " in addition to being used to illustrate embodiments above about PI3K, can also be in the same manner using taking office What his relevant protein/polypeptide/enzyme.

Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.

Term used in the present invention " biological sample " refers to the sample of vitro, including but not limited to, cell training Feeding or cell extraction；The biopsy substance obtained from mammal or its extract；Blood, saliva, urine, excrement, essence Liquid, tears or other living tissue liquid substances and its extract.Inhibiting kinase activity in biological sample, especially PI3K is active, It can be used for multiple use well known to one of ordinary skill in the art.Such purposes includes, but is not limited to, hematometachysis, and organ moves It plants, biological sample storage and bioassay.

When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used to block or protect the functionality of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group can refer to document: T W.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.

The description of the compound of the present invention

The invention discloses a new class of compounds, can be used as kinase activity inhibitor, especially can be used as PI3- kinases Active inhibitor.Compound as PI3- kinase inhibitor can be used for treating and unsuitable kinase activity, especially not The associated disease of PI3- kinase activity appropriate, such as treating and preventing by the disease of PI3- kinases mechanisms mediate.In this way Disease include respiratory disease, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)；Virus Infection, including viral respiratory infection and viral respiratory disease deteriorate, such as asthma and COPD；Non-viral respiratory tract sense Dye, including aspergillosis and leishmaniasis；Allergic diseases, including allergic rhinitis and atopical dermatitis；Autoimmunity Property disease, including rheumatoid arthritis and multiple sclerosis；Inflammatory disease, including inflammatory bowel disease；Cardiovascular disease, including blood Bolt disease and atherosclerosis；Malignant hematologic disease；Neurodegenerative disease；Pancreatitis；Multiple organ failure；Nephrosis；Platelet aggregation Collection；Cancer；Sperm motility；Graft rejection；Graft rejection；Injury of lungs；And pain, including closed with rheumatoid arthritis or bone Neuralgia, diabetic neuropathy, neuro-inflammatory pain after the scorching relevant pain of section, backache, systemic inflammatorome pain, liver (wound), trigeminal neuralgia and central pain bitterly.

In some embodiments, the compounds of this invention can show that the selectivity of PI3- kinases be more than other class type kinases.

In other embodiment, the compounds of this invention can be used as effective inhibitor of PI3K δ.

In other embodiment, the compounds of this invention can show that the selectivity of PI3K δ be more than other types PI3- Kinases.

On the one hand, the present invention relates to a kind of compound, chemical combination shown in the compound or formula (I) for structure shown in formula (I) The stereoisomer of object, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:

Wherein: each X, Y, R³And R⁴With definition as described in the present invention.

In some embodiments, X H, C_1-12Alkyl, C_3-12Naphthenic base, C_6-12Aryl, 3-12 former molecular heterocycle Base or 5-12 former molecular heteroaryl, wherein each C_1-12Alkyl, C_3-12Naphthenic base, C_6-12Aryl, 3-12 atom The former molecular heteroaryl of the heterocycle of composition and 5-12 is individually optionally by 1,2,3,4 or 5 R¹Replaced group；

R¹For H, F, Cl, Br, CN, NO₂, oxo (=O) ,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b,-OC (= O)NR^aR^b,-OC (=O) OR^a,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-S (=O)₂R^a,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4It is sub- Alkyl, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (=O) O-C_1-4Alkylene Base, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN- C_1-4Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 3-12 atom group At heterocycle, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 The molecular heteroaryl of a original or (5-10 former molecular heteroaryl)-C_1-4Alkylidene, wherein each C_1-6Alkyl, C_2-6 Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 3-12 former molecular heterocycle, (3-12 atom The heterocycle of composition)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl)-C_1-4Alkylidene is independently unsubstituted or replaced 1,2,3 or 4 substituent group, institute Substituent group is stated independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；

Y is monocycle or bicyclic system comprising at least one N atom, and the monocycle is armaticity, and described bicyclic At least one ring is armaticity in system, wherein the Y is optionally by 1,2,3,4 or 5 R²Replaced group；

R²For H, F, Cl, Br, CN, NO₂, oxo (=O) ,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b,-OC (= O)NR^aR^b,-OC (=O) OR^a,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-S (=O)₂R^a,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4It is sub- Alkyl, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (=O) O-C_1-4Alkylene Base, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN- C_1-4Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, (3-12 atom group At heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, the molecular heteroaryl of 5 originals or (5-10 Former molecular heteroaryl)-C_1-4Alkylidene, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8 Naphthenic base-C_1-4Alkylidene, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylene Base, 5 molecular heteroaryls of original and (5-10 former molecular heteroaryl)-C_1-4Alkylidene it is independently unsubstituted or by Replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO- C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；

When Y is 4- quinazolinone, R²It is not phenyl；

Each R³And R⁴It independently is H, F, CN ,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b, R^bR^aNC (=O)-C_1-4 Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (=O) O-C_1-4Alkylene Base, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^bS (=O)₂N(R^c)-C_1-4Alkylidene, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4Alkylene Base, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 3-12 former molecular heterocycle Base, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 atom group At heteroaryl or (5-10 former molecular heteroaryl)-C_1-4Alkylidene, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6 Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 3-12 former molecular heterocycle, (3-12 former molecular miscellaneous Ring group)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 original Molecular heteroaryl)-C_1-4Alkylidene is independently unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group Independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；Or R³, R⁴With Together with the carbon atom being connected with them, the former molecular carbocyclic ring of substituted or non-substituted 3-8 or heterocycle are formed；With

Each R^a, R^bAnd R^cIt independently is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-4It is sub- Alkyl, 3-12 former molecular heterocycle, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Virtue Base-C_1-4Alkylidene, 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C_1-4Alkylidene, wherein Each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-4Alkylidene, 3-12 former molecular Heterocycle, (3-12 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former Molecular heteroaryl and (5-10 former molecular heteroaryl)-C_1-4Alkylidene is independently unsubstituted or by 1,2,3 or 4 Replaced a substituent group, the substituent group is independently selected from F, Cl, CN, N₃, OH, NH₂, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkane Oxygroup or C_1-6Alkyl amino；Or R^a, R^bTogether with the nitrogen-atoms being connected with them, it is former to form substituted or non-substituted 3-8 Molecular heterocycle.

In other embodiment, X C_1-6Alkyl, C_3-8Naphthenic base, C_6-10Aryl, 3-7 former molecular heterocycle Base or 5-10 former molecular heteroaryl, wherein each C_1-6Alkyl, C_3-8Naphthenic base, C_6-10Aryl, 3-7 atom group At heterocycle and 5-10 former molecular heteroaryl individually optionally by 1,2,3 or 4 R¹Replaced group.

In other embodiment, R¹For H, F, Cl, CN, oxo (=O) ,-C (=O) OR^a,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4 Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 4-7 former molecular Heterocycle, (4-7 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former Molecular heteroaryl or (5-10 former molecular heteroaryl)-C_1-4Alkylidene, wherein each C_1-6Alkyl, C_2-6Alkene Base, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, 4-7 former molecular heterocycle, (4-7 atom composition Heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 A molecular heteroaryl of original)-C_1-4Alkylidene is independently unsubstituted or replaced 1,2,3 or 4 substituent group, described to take Dai Ji is independently selected from F, Cl, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene.

In other embodiment, Y is the bicyclic system comprising at least one N atom, and in the bicyclic system At least one ring is armaticity, wherein the Y is optionally by 1,2,3 or 4 R²Replaced group；When Y is 4- quinazoline When ketone, R²It is not phenyl.

In other embodiment, R²For H, F, Cl, CN, oxo (=O) ,-C (=O) OR^a,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4 Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Naphthenic base-C_1-4Alkylidene, (4-7 former molecular Heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, the molecular heteroaryl of 5 originals or (5-10 atom The heteroaryl of composition)-C_1-4Alkylidene, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_3-8Cycloalkanes Base-C_1-4Alkylidene, (4-7 former molecular heterocycle)-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5 Former molecular heteroaryl and (5-10 former molecular heteroaryl)-C_1-4Alkylidene it is independently unsubstituted or by 1,2,3 or Replaced 4 substituent groups, the substituent group is independently selected from F, Cl, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene.

In other embodiment, each R³And R⁴It independently is H, F, CN ,-C (=O) NR^aR^b, R^bR^aNC (=O)-C_1-2 Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-2Alkylidene, R^aOC (=O) N (R^c)-C_1-2Alkylidene, R^bR^aNC (=O) O-C_1-2Alkylene Base, R^bR^aNS (=O)₂-C_1-2Alkylidene, R^bS (=O)₂N(R^c)-C_1-2Alkylidene, R^aO-C_1-2Alkylidene, R^bR^aN-C_1-2Alkylene Base, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-2Alkylidene, 4-7 former molecular heterocycle Base, (4-7 former molecular heterocycle)-C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, 5 molecular heteroaryls of original Or (5 molecular heteroaryls of original)-C_1-2Alkylidene, wherein each C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkanes Base, C_3-6Naphthenic base-C_1-2Alkylidene, 4-7 former molecular heterocycle, (4-7 former molecular heterocycle)-C_1-2Alkylene Base, phenyl, phenyl-C_1-2Alkylidene, 5 molecular heteroaryls of original and (5 molecular heteroaryls of original)-C_1-2Alkylidene is only On the spot unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；Or R³, R⁴Together with the carbon atom being connected with them, shape At substituted or non-substituted 3-8 former molecular carbocyclic ring or heterocycle.

In other embodiment, each R^a, R^bAnd R^cIt independently is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Ring Alkyl, C_3-6Naphthenic base-C_1-4Alkylidene, 4-7 former molecular heterocycle, 4-7 former molecular heterocycle-C_1-4Alkylene Base or 5-10 former molecular heteroaryl, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, C_3-6Ring Alkyl-C_1-4Alkylidene, 4-7 former molecular heterocycle, (4-7 former molecular heterocycle)-C_1-4Alkylidene and 5-10 A molecular heteroaryl of original is independently unsubstituted or replaced 1,2,3 or 4 substituent group, and the substituent group independently selects From F, CN, N₃, OH, NH₂, C_1-3Alkyl, C_1-3Halogenated alkyl, C_1-4Alkoxy or C_1-4Alkyl amino；Or R^a, R^bWith with their phases With nitrogen-atoms together with, form substituted or non-substituted 3-6 former molecular heterocycle.

In other embodiment, X C_1-4Alkyl, C_3-6Naphthenic base, phenyl, 3-6 former molecular heterocycle or 5-6 former molecular heteroaryl, wherein each C_1-4Alkyl, C_3-6Naphthenic base, phenyl, 3-6 former molecular heterocycle With 5-6 former molecular heteroaryl it is individually optional by 1,2,3 or 4 R¹Replaced group.

In other embodiment, R¹For H, F, Cl, CN, oxo (=O) ,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-N (R^c) S (=O)₂R^a, R^bR^aNC (=O)-C_1-2Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-2Alkylidene, R^bR^aNS (=O)₂-C_1-2Alkylidene, OR^a, NR^aR^b, R^aO-C_1-2Alkylidene, R^bR^aN-C_1-2It is sub- Alkyl, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-2Alkylidene, 4-6 former molecular miscellaneous Ring group, (4-6 former molecular heterocycle)-C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, 5-6 former molecular miscellaneous Aryl or (5-6 former molecular heteroaryl)-C_1-2Alkylidene, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-2Alkylidene, 4-6 former molecular heterocycle, (4-6 former molecular heterocycle)- C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, 5-6 former molecular heteroaryl and (the 5-6 molecular heteroaryl of original)- C_1-2Alkylidene is independently unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from F, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-2Alkylidene or R^bR^aN-C_1-2Alkylidene.

In other embodiment, Y is

Wherein, W independently is N or CH, and the Y is optionally by 1,2,3 or 4 R²Replaced group；When W is N, R²It is not phenyl.

In other embodiment, R²For H, F, Cl, CN, oxo (=O) ,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-N (R^c) S (=O)₂R^a, R^bR^aNC (=O)-C_1-2Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-2Alkylidene, R^bR^aNS (=O)₂-C_1-2Alkylidene, OR^a, NR^aR^b, R^aO-C_1-2Alkylidene, R^bR^aN-C_1-2It is sub- Alkyl, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-2Alkylidene, (4-6 former molecular miscellaneous Ring group)-C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, the molecular heteroaryl of 5 originals or (5-6 former molecular heteroaryl Base)-C_1-2Alkylidene, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6Naphthenic base-C_1-2Alkylene Base, (4-6 former molecular heterocycle)-C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, 5 molecular heteroaryls of original (5-6 former molecular heteroaryl)-C_1-2Alkylidene is independently unsubstituted or replaced 1,2,3 or 4 substituent group, The substituent group is independently selected from F, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-2Alkylidene or R^bR^aN-C_1-2Alkylidene.

In other embodiment, each R³And R⁴It independently is H, F, CN, C_1-3Alkyl, C_3-6Naphthenic base, 4-6 atom The heterocycle of composition or (4-6 former molecular heterocycle)-C_1-2Alkylidene, wherein each C_1-3Alkyl, C_3-6Naphthenic base, 4-6 former molecular heterocycle and (4-6 former molecular heterocycle)-C_1-2Alkylidene is independently unsubstituted or by 1, Replaced 2,3 or 4 substituent groups, the substituent group is independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-2 Alkylidene or R^bR^aN-C_1-2Alkylidene；Or R³, R⁴Together with the carbon atom being connected with them, substituted or non-substituted 3- is formed The molecular carbocyclic ring of 6 originals or heterocycle.

In other embodiment, each R^a, R^bAnd R^cIt independently is H, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Ring Alkyl, C_3-6Naphthenic base-C_1-2Alkylidene, 4-6 former molecular heterocycle, (4-6 former molecular heterocycle)-C_1-2It is sub- Alkyl or 5-6 former molecular heteroaryl, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, C_3-6 Naphthenic base-C_1-2Alkylidene, 4-6 former molecular heterocycle, (4-6 former molecular heterocycle)-C_1-2Alkylidene and 5-6 A molecular heteroaryl of original is independently unsubstituted or replaced 1,2,3 or 4 substituent group, and the substituent group independently selects From F, CN, N₃, OH, NH₂, C_1-3Alkyl, C_1-3Halogenated alkyl, C_1-3Alkoxy or C_1-3Alkyl amino；Or R^a, R^bWith with their phases With nitrogen-atoms together with, form substituted or non-substituted 5-6 former molecular heterocycle.

In other embodiment, Y is

Wherein, W CH, and the Y is optionally by 1,2 or 3 R²Replaced group.

In other embodiment, Y is

Wherein, W N, and the Y is optionally by 1,2 or 3 R²Replaced group.

It is several the present invention relates to the compound of one of or its stereoisomer in other embodiment What isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, but It is not limited to these compounds:

On the other hand, the present invention is provided to the method for -3 kinases of inhibition of phosphatidylinositol3 (PI3- kinases), this method packets It includes: contacting PI3- kinases with a effective amount of compound disclosed in this invention；In some embodiments, contact procedure can be into One step includes the cell of contact expression PI3- kinases；In the other embodiment of this method, inhibiting effect generation is being endured In the object of one or more type PI3- kinases obstacle related diseases.One or more type PI3- according to the present invention swash The relevant disease of enzyme obstacle includes autoimmune disease, rheumatic arthritis, respiratory disease, allergic reaction and various The cancer of type.

In some embodiments, method of the present invention includes applying second therapeutic agent to object.

In other embodiments, PI3- kinase mediated disease is selected from rheumatic arthritis, ankylosing spondylitis, and bone closes Section is scorching, psoriatic arthritis, psoriasis, diseases associated with inflammation and autoimmune disease；Other embodiments, PI3- kinases are situated between The disease led is selected from cardiovascular disease, atherosclerosis, hypertension, Deep vain thrombosis, apoplexy, myocardial infarction, shakiness Centering colic pain, thromboembolism, pulmonary embolism, thrombolysis disease, Acute arterial ischeamia, peripheral thrombus obstruction and coronary artery disease.Separately Some embodiments, PI3- kinase mediated disease are selected from cancer, colon cancer, glioblastoma, carcinoma of endometrium, liver cancer, lung Cancer, melanoma, kidney, thyroid cancer, lymthoma, lymphoproliferative disorder, Small Cell Lung Cancer, prognosis of squamous cell lung cancer, colloid Tumor, breast cancer, prostate cancer, oophoroma, cervical carcinoma and leukaemia.In other embodiments, PI3- kinase mediated disease Selected from type-2 diabetes mellitus；In other embodiments, PI3- kinase mediated disease is selected from respiratory disease, and bronchitis is roared Asthma and chronic obstructive pulmonary disease；In other embodiments, object is people.

On the other hand, the present invention relates to the treatment of PI3- kinase mediated disease, the treatment includes any of above embodiment party The dosing step of the compound of case.

On the other hand, the present invention relates to rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, The treatment of psoriasis, diseases associated with inflammation or autoimmune disease, the treatment include the compound of any of above embodiment Dosing step.

On the other hand, the present invention relates to include asthma, Chronic Obstructive Pulmonary Disease (COPD) and idiopathic pulmonary fibrosis (IPF) etc. the treatment of respiratory diseases, the treatment include the dosing step of the compound of any of above embodiment.

On the other hand, the present invention relates to inflammatory bowel disease, inflammatory ocular disease, inflammation or unstable bladder disease, The skin disease of inflammatory component, chronic inflammation, systemic loupus erythematosus (SLE), myasthenia gravis, acute diseminated encephalomyelitis, Idiopathic blood platelet reduction property purpura, multiple sclerosis, Sjogren syndrome and autoimmune hemolytic anemia, mistake The treatment of quick property and pleoergy, the treatment include the dosing step of the compound of any of above and following embodiment.

On the other hand, involved in the present invention to be mediated by PI3K activity, it is active or relevant to PI3K activity dependent on PI3K The treatment of cancer, the especially activity of PI3K δ, the treatment include the administration of the compound of any of above and following embodiment Step.

On the other hand, the present invention relates to the treatments for being selected from following cancer: acute myelogenous leukemia, spinal cord development are extremely comprehensive Simulator sickness, myeloproliferative disease, chronic myelogenous leukemia, T cell acute lymphoblastic leukemia, B cell acute lymphoblastic are white Blood disease, non-Hodgkin lymphoma, B cell lymphoma, solid tumor and breast cancer, described treat includes any of above and following embodiment party The dosing step of the compound of case.

On the other hand, the present invention relates to the compounds of any of above embodiment as the application in terms of drug.

On the other hand, the therapeutic agent system disease mediated in PI3K the present invention relates to the compound of any of above embodiment Make the application of aspect.

On the other hand, the present invention relates to the compounds of any of above embodiment treats rheumatoid arthritis in preparation, Ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation, including asthma, Chronic Obstructive Pulmonary Disease Disease respiratory diseases, autoimmune disease and the cancer such as (COPD) and idiopathic pulmonary fibrosis (IPF).

Unless otherwise stated, the present invention relates to the stereoisomer of all the compounds of this invention, geometric isomer mutually makes a variation Structure body, solvate, hydrate, metabolite, salt and pharmaceutically acceptable prodrug.

In some embodiments, the salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to object Matter or composition must be with other ingredients comprising preparation and/or the mammal treated with it chemically and/or in toxicology It is compatible.

The compound of the present invention further includes other salt of such compound, which is not necessarily pharmaceutically acceptable Salt, and may be used as being used to prepare and/or purify the compound of the present invention and/or for separating the compound of the present invention The intermediate of enantiomer.

Pharmaceutical acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Object/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

The inorganic acid that salt can be obtained by its derivative includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.

The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

Can obtain the inorganic base of salt by its derivative includes, for example, ammonium salt and periodic table I race to XII race metal.? In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.

It includes naturally occurring that the organic base that can obtain salt by its derivative, which includes primary amine, secondary amine and tertiary amine, substituted amine, Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.

Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate etc.) reaction, or free alkali form and chemistry meter by making these compounds The suitable acid reaction of amount amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both.One As, in appropriate cases, need using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.In example Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.

Moreover, the compounds of this invention including its salt can also be obtained in the form of its hydrate, or it is used for including other The solvent of crystallization.The compounds of this invention can form the solvation with acceptable solvent (including water) inherently or by design Object；Therefore, the invention is intended to include solvated and unsolvated forms.

On the other hand, the present invention provides the preparation of compound shown in formula (I), the methods of separation and purifying.Of the present inventionization Closing object might have the form at several asymmetric centers or usually described raceme mixture.The present invention further wraps Containing racemic mixture, the mixture of partial racemization and isolated enantiomer and diastereomer.

The compound of the present invention can be in possible isomers, rotational isomer, atropisomer, tautomer A kind of form of or mixtures thereof form exists, and the present invention can further include isomers, rotational isomer, resistance turn isomery Body, the mixture of tautomer or isomers, rotational isomer, atropisomer, tautomer part mixes Or isomers, rotational isomer, atropisomer, the tautomer separated.

Any structural formula that the present invention provides is also intended to the form and isotope mark for indicating that these compounds are not labeled The form of note.The structure that the general formula that there is the compound of isotope labelling the present invention to provide is described, in addition to one or more atoms By the atom replacement with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention include Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, such as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁸F,³¹P,³²P,³⁶S,³⁷Cl or¹²⁵I。

On the other hand, compound of the present invention includes compound defined in the present invention with various isotope labellings, For example, wherein there is radioactive isotope, such as³H,¹⁴C and¹⁸Those of F compound, or wherein there is non radioactive isotope, Such as²H and¹³C.The compound of such isotope labelling can be used for being metabolized research and (use¹⁴C), Reaction kinetics research (use example Such as²H or³H), detection or imaging technique are surveyed such as positron emission tomography (PET) or including drug or substrate tissue distribution Fixed single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound pair of F label It is especially desirable for PET or SPECT research.Formula (I) compound of isotope labelling can pass through those skilled in the art Known routine techniques or embodiment in the present invention and preparation process are described is substituted using suitable isotope labeling reagent Originally prepared by used unmarked reagent.

In addition, higher isotope especially deuterium (that is,²H or D) substitution can provide certain treatment advantages, these advantages are By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in this context is seen as the substituent group of formula (I) compound.Isotope enrichment factor can be used To define the concentration of such higher isotope especially deuterium.Term " isotope enrichment factor " used in the present invention refers to meaning Determine the ratio between the isotope abundance of isotope and natural abundance.If the substituent group of the compounds of this invention is designated as deuterium, The compound at least 3500 (52.5% deuterium incorporation at each specified D-atom), at least for each specified D-atom 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutical solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution₂O, acetone-d₆、 Or DMSO-d₆Those of solvate.

The composition of the compound of the present invention, preparation and administration

On the one hand, the characteristics of pharmaceutical composition of the invention includes formula (I) compound represented, change listed by the present invention Close object or the compound and pharmaceutically acceptable carrier of embodiment 1-14, adjuvant or excipient.In composition of the invention The amount of compound can effectively, detectably inhibit the protein kinase of biological sample or patient's body.

The compound of the present invention exists in a free form or in the form of suitable, pharmaceutically acceptable derivates.Pharmacy Upper acceptable derivates include, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, esters salt, can directly or Be grounded other any adducts being administered according to needs of patient or derivative, the present invention in terms of other described in compound or Their metabolite or residue.

As described in the invention, pharmaceutical composition of the present invention or pharmaceutically acceptable composition further wrap Containing pharmaceutically acceptable carrier, adjuvant or excipient, as applied by the present invention, including it is suitable for distinctive target formulation , any solvent, diluent, liquid excipient, dispersing agent, suspending agent, surfactant, isotonic agent, thickener, emulsifier, Preservative, solid binder or lubricant, etc..As described in following documents: Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams& Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology, Eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, document above disclose It is for reference that content is incorporated in the present invention in its entirety.Literature cited, which describes, herein is used to prepare pharmaceutically acceptable combination Preparation method well known to the different carriers and composition of object.In addition to the conventional carrier matchmaker incompatible with the compound of the present invention It is situated between, such as bad biological effect can be generated or harmful phase occurs with any other component in pharmaceutically acceptable composition Interaction, other any conventional carrier mediums and their purposes are also the range that the present invention is considered.

Pharmaceutical composition of the invention can prepare and be packaged as form in bulk, wherein extractable safely, effectively agent out Compound or its pharmaceutically acceptable salt shown in the formula (I) of amount, can be administered to a patient in the form of powder or syrup.Or Person, pharmaceutical composition of the present invention can be prepared or be packaged in unit dosage forms, wherein each unit dosage forms contain shown in formula (I) Compound or its pharmaceutically acceptable salt.When being prepared into unit dosage forms, pharmaceutical composition of the invention usually contains 0.5mg To formula (I) compound represented of 1g or 1mg to 700mg or 5mg to 100mg or its pharmaceutically acceptable salt.

Pharmaceutical composition of the invention typically contains formula (I) compound represented or its pharmaceutically acceptable salt.

Term " pharmaceutically acceptable excipient " in the present invention refers to and gives pharmaceutical composition shape or compatibility Pharmaceutically acceptable material, composition or carrier.In mixing, every kind of excipient must be with other in pharmaceutical composition Component is compatible, thus the effect of avoiding when giving patient, substantially reducing the compounds of this invention or its pharmaceutically acceptable salt And lead to the interaction of pharmaceutically unacceptable composition.In addition, every kind of excipient must all have sufficiently high purity So that it is pharmaceutically acceptable.Formula (I) compound represented or its pharmaceutically acceptable salt and pharmaceutically acceptable Excipient or adjuvant are usually formulated as being suitable for giving the dosage form with patient by required administration route.For example, be suitable for The dosage form of lower administration route: (1) be administered orally, as tablet, capsule, caplet agent, pill, containing tablet, pulvis, syrup, elixir, Suspension, solution, emulsion, sachet and sachet；(2) parenteral, as sterile solution agent, suspension and for redissolution Pulvis；(3) percutaneous dosing, such as transdermal patch；(4) rectally, such as suppository；(5) inhalation, as aerosol, solution and Dry powder doses；(6) local administration, such as cream, ointment, washing lotion, solution, paste, spray, foaming agent and gelling agent.

Suitable pharmaceutically acceptable excipient is different by the selected specific dosage form of view.In addition, can be for them in group The specific function that plays is closed in object to select suitable pharmaceutically acceptable excipient.For example, can help to give birth to according to them It produces the ability of equal one dosage type low temperature and selects certain pharmaceutically acceptable excipient.It can facilitate for them when giving patient The compounds of this invention or its pharmaceutically acceptable salt are carried or transported from an organ of human body or partially to the another of human body A organ or partial ability select certain pharmaceutically acceptable excipient.The energy of patient compliance can be enhanced for them Power selects certain pharmaceutically acceptable excipient.

Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, adhesive, Disintegrating agent, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.It would be recognized by those skilled in the art that certain pharmaceutically acceptable excipient can play it is more In a kind of function, and alternative function can be played, this is depended in the formulation, and there are what in the presence of how much excipient and preparation Kind other compositions.

Those skilled in the art grasp the knowledge and technology of this field, they are selected for of the invention appropriate Amount, suitable, pharmaceutically acceptable excipient.In addition, those skilled in the art can pharmaceutically connect from many descriptions The place for the excipient received obtains resource, and can be used for selecting suitable pharmaceutically acceptable excipient.Such as: Remington′s Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。

Pharmaceutical composition of the present invention is prepared using technique well known by persons skilled in the art and method.Commonly used in the art Certain methods can refer to: Remington ' s Pharmaceutical Sciences (Mack Publishing Company).

On the other hand, it is prepared comprising formula (I) compound represented or its is pharmaceutically acceptable the present invention relates to a kind of Salt and one or more pharmaceutically acceptable excipient containing mixed component pharmaceutical composition method.It is this to include One formula (I) compound represented or the pharmaceutical composition of its pharmaceutically acceptable salt can be made under room temperature, condition of normal pressure It is standby to obtain.

In some embodiments, formula (I) compound represented or its pharmaceutically acceptable salt be prepared to take orally to The dosage form of medicine.In other embodiments, formula (I) compound represented or its pharmaceutically acceptable salt are prepared to suck The dosage form of administration.In other embodiments, formula (I) compound represented or its pharmaceutically acceptable salt are prepared to fit In the dosage form of nasal-cavity administration.

On the one hand, the present invention relates to solid oral administrations dosage forms, such as: tablet or capsule, it includes safely, effectively Formula (I) compound represented or its pharmaceutically acceptable salt, diluent or filler of dosage.Suitable diluent and filling Agent includes: lactose, sucrose, glucose, mannitol, D-sorbite, (e.g., cornstarch, potato starch and pregel form sediment starch Powder), calcium sulfate, calcium monohydrogen phosphate.Oral dosage form can also further include adhesive.Suitable adhesive includes starch (e.g., cornstarch, potato starch and pregelatinized starch), gelatin, Arabic gum, sodium alginate, alginic acid, tragacanth, melon That glue, povidone, cellulose and their derivative (e.g., microcrystalline cellulose).Oral dosage form can also include disintegrating agent. Suitable disintegrating agent includes crospovidone, sodium starch glycolate, cross-linked carboxymethyl cellulose, alginic acid, carboxymethyl cellulose Plain sodium.Oral solid dosage dosage form can also include lubricant.Suitable lubricant includes magnesium stearate, calcium stearate, tristearin Acid and talcum powder.

If appropriate, microencapsulation can be carried out to the dosage unit preparations of oral administration.By the way that particulate matter is coated Or in being embedded in polymer, wax etc., it can extend or control the release of the pharmaceutical composition.

Formula (I) compound represented or its pharmaceutically acceptable salt can also be with the solubilities as target medicine carrier Polymer coupling.Suitable polymer includes: polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide- Cascophen, polyhydroxyethylaspart or the polyoxyethylene poly-D-lysine replaced by palmitic acid residues.In addition, Formula (I) compound represented or its pharmaceutically acceptable salt can also with a series of achievable controlled release drug administrations, can biology drop The polymer of solution combines.Such as: polylactic acid, polycaprolactone, multi-hydroxybutyrate, polyorthoester, polyacetals, poly- dihydropyran, The crosslinking of polybutylcyanoacrylate and hydrogel or amphiphilic block copolymer.

On the other hand, the present invention relates to liquid oral form of administration.Liquid oral dosage form, such as: solution, syrup, Elixir can be made in a unit, in such a given metering containing the compounds of this invention of predetermined amount or its Pharmaceutically acceptable salt.Syrup is that the compounds of this invention or its pharmaceutically acceptable salt are dissolved in suitably seasoned water It is made in solution, and elixir is made by using nontoxic alcoholic vehicle.Suspension is by the compounds of this invention or its pharmacy Upper acceptable salt, which is suspended in non-toxic carrier, to be made.Can also be added solubilizer and emulsifier such as ethoxylated isostearyl alcohol and Polyoxyethylene sorbitol ether, preservative, flavoring agent such as peppermint oil, natural sweetener or saccharin or other artificial sweeteners etc..

On the other hand, the present invention relates to a kind of dosage form that can carry out inhalation to patient, as dry powder doses, aerosol, Suspension or liquid composite.In some embodiments, the present invention relates to the dosage forms that inhalation can be carried out to patient, such as Dry powder doses.In other embodiments, the present invention relates to carry out inhalation in aerosol to patient.Pass through sucking Mode contain the compounds of this invention or its pharmaceutically acceptable salt of fine powder form to the dry powder composite of pulmonary administration With one or more pharmaceutically acceptable excipient of fine powder form.To those skilled in the art, particularly suitable The pharmaceutically acceptable excipient used in dry powder doses includes lactose, starch, mannitol, monosaccharide, disaccharides or polysaccharide.Point Dissipating good powder can be obtained by way of micronized and grinding.In general, size reduces (such as micronized) chemical combination The size of object is by D₅₀Value limits, and about 1 to 10 microns (for example, being measured with laser diffractometry).

The dry powder can be administered to a patient by the inhalator (RDPI) of reservoir dry powder, which, which has, is suitable for storage Deposit (non-dosing) drug reservoir of multiple dry powder forms.RDPI generally include to measure from storage each drug dose to The equipment of medicine position.For example, the measuring equipment may include jigger, it can be moved to the second position from first position, At first position, jigger can be full of the drug from storage, and in the second place, the drug dose measured can be by patient Sucking.

Alternatively, the dry powder can be stored in capsule (e.g., gelatin or plasthetics), cylindrantherae or blister pack For multidose dry powder inhaler (MDPI) use in (blister packs).MDPI is inhalator, and wherein drug is comprised in Containing (or carry) multiple limiting doses (or part thereof) in the multiple-unit container of drug.When the dry powder is with blister pack In the presence of form, it includes multiple bubble-caps (blister) containing dry powder form medicament.Typically, the bubble-cap is with rule side Formula arrangement, to facilitate from wherein discharging drug.For example, the bubble-cap can usually be arranged in collar plate shape bubble-cap in a circular manner In packaging or the bubble-cap can be to be elongated, for example including strip or band-like.Each capsule, cylindrantherae or bubble-cap can be such as The compounds of this invention or its pharmaceutically acceptable salt containing 20 μ g-10mg.

Aerosol can be suspended or dissolved in liquefaction and promote by by the compounds of this invention or its pharmaceutically acceptable salt It is prepared in agent.Suitable propellant includes halogenated hydrocarbons, hydro carbons and other liquefied gases.Representative propellant includes: Trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1- Difluoroethane (HFA-152a), methylene chloride (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, perfluorinated butane, perflenapent, butane, iso-butane and pentane.Comprising the compounds of this invention or its The aerosol of pharmaceutically acceptable salt is administered to a patient typically via quantitative pressure inhalator (MDI).These devices are these Known to the technical staff of field.

Aerosol can excipient that is pharmaceutically acceptable containing other, being typically used together with MDI such as surface work Property agent, lubricant, cosolvent and other excipient to improve the physical stability of preparation improve valve performance, improve dissolution Degree improves taste.

Therefore, the present invention provides the medicinal aerosols as another aspect of the present invention, and it includes chemical combination of the present invention Object or its pharmaceutically acceptable salt and fluorocarbon, hydrogeneous chlorofluorocarbons are as propellant, optional and surfactant And/or cosolvent combines.

According to another aspect of the present invention, the present invention provides a kind of medicinal aerosol, propellant is selected from 1,1,1,2- tetra- Fluoroethane, the mixture of 1,1,1,2,3,3,3- seven fluorine n-propane and they.

Suitable buffer buffering can also be added in preparation of the invention.

For sucking or being blown into the capsule and cylindrantherae of administration, such as gelatina can be configured to containing the powder for being suitable for sucking The preparation of mixture, the mixture of powders include the compounds of this invention or its pharmaceutically acceptable salt and suitable mealiness base Matter, such as lactose or starch.Each capsule and cylindrantherae usually contain the compounds of this invention of 20 μ g-10mg or its is pharmaceutically acceptable Salt.In addition, capsule or cylindrantherae can contain only the compounds of this invention or its pharmaceutically acceptable salt and be free of other figurations Agent such as lactose.

The ratio of reactive compound of the present invention or its pharmaceutically acceptable salt in topical composition depends on institute The specific dosage form of preparation, usually ratio used is within the scope of the weight ratio of 0.001-10%.Typically for most of doses Suitable proportion used in type is from 0.005%~1%, such as is out of 0.01%-0.5% in some embodiments. But ratio used in the powder in inhalant and insufflation is in the range of 0.1%-5%.

The preferred dosage formulation of aerosol is that the unit metered dose of aerosol or " penetrating " dosage is made to contain 20 μ g- 10mg, the preferably approximately salt of the compounds of this invention of 20 μ -500 μ g or its pharmaceutical acceptable.Administration can be once a day Or one day for several times, such as 2,3,4 or 8 times, administration is such as 1,2 or 3 unit dose every time.The total daily dose of aerosol is in 100 μ g- 10mg, preferably in the range of 200 μ g-2000 μ g.Capsule or cylindrantherae are to suck or be blown into the total daily dose that administration discharges The dosage of aerosol is usually twice in metered dose.

In suspension aerosol, the granule size of particle (such as particle) should meet with aerosol form inhalation Afterwards, whole drugs can enter lung；Therefore, partial size should be less than 100 microns, and preferably partial size is less than 20 microns, especially It is partial size at 1-10 microns, such as 1-5 microns, preferably partial size is in the range of 2-3 microns.

Dosage form of the invention can by appropriate containers by drug and the compounds of this invention or its is pharmaceutically acceptable Salt be dispersed or dissolved in propellant and prepare, such as assisted using sonication or high-shear mixer.The preparation Journey will carry out in the environment of control air humidity.

The chemistry of aerosol of the invention, physical stability and acceptability pharmaceutically can be by those skilled in the art It is measured using techniques well known.For example, compound, after long-term storage, stability can be analyzed by HPLC and be measured. Physical stability data can be obtained by other conventional analysis test methods, for example, being commented by leak test, valve for medicine Fixed (opening the weight averagely released every time), dose reproducibility evaluation (opening the active principle released every time) and spray Distributional analysis.

The stability of suspension aerosol of the invention can be measured by routine techniques, for example, passing through measurement floccules Degree distribution, using back-illuminated light scattering apparatus or by measurement particle size distribution, by colliding (cascade impaction) step by step Or " binary collision " (twin impinger) assay." binary collision " measuring method of the present invention refers to that " use device A exists In pressurizing vessel measurement eject medicament precipitating ", this definition is shown in British Pharmacopoeia 1988, the A204-207 pages, annex XVII C.This technology can calculate the inhalable particle part in aerosol.One kind is for calculating inhalable particle Method be this is using above-mentioned " binary collision " by " fine grained classification " method, open every time from collision cell collective low to Active constituent amount, be expressed as opening the percentage of the active constituent total amount ejected every time.

Term " metered dose inhaler " or MDI refer to a combination, the protection cap covered comprising a tank, one in tank, He Gai Formula metering valve on son.MDI system includes suitable transfer device.Suitable transfer device includes a such as valve driving Device, a cylindric or coniform channel can be transmitted to patient from filling tank by metering valve by this channel drug Nose or mouth in, such as blow gun actuator.

MDI tank generally comprises the container that can bear propellant vapour pressure, e.g., plastics or plastic-faced vial Preferably metal can, for example, aluminium pot or aluminium alloy can, it can be by anodization, varnish application and/or plastics Coating, (for example, introducing bibliography patent WO 96/32099 herein, part of or all inner surface is coated with one Or multiple fluorocarbon polymers and one or more non-fluorocarbon polymers), container metering jam pot cover mouth.Lid can be by super The mode that sound wave welding, screw are fixed or crimped is fixed on tank.MDI (dose inhaler) shown in this article can pass through this field (referenced patent WO96/32099) is made in known method.Preferably, it is furnished with lid on cylindrantherae, wherein medication dosing valve is located at lid On son, the lid is crimped on cylindrantherae.

In some embodiments of the invention, one layer of fluoropolymer is coated by the metallic interior surface of tank, more preferably, Coating is the mixture of fluoropolymer and non-fluorinated polymer.In other embodiments of the invention, the metallic interior surface of tank Copolymer mixture coated with polytetrafluoroethylene (PTFE) and polyethersulfone resin.In other embodiments, table in the entire metal of tank Face is each coated with the copolymer mixture of polytetrafluoroethylene (PTFE) and polyethersulfone resin.The design of metering valve is intended to open every time and all can provide The dosage form of metering, and the washer for preventing propellant from leaking from valve containing one.Washer may include any suitable bullet Property material, for example, low density polyethylene (LDPE), chlorobutyl, brombutyl, ethylene propylene diene rubber, black or white butadiene-acrylonitrile Rubber, butyl rubber and neoprene.Suitable valve can be bought from manufacturer well known to aerosol industry to be obtained, such as Valois, French (such as DF10, DF30, DF60), Bespak pic, Britain such as (BK300, BK357) and 3M-TM Neotechnic Ltd, Britain (such as Spraymiser).

In various embodiments, metered dose inhaler can also be used for being incorporated in other structures, such as, but not limited to, be used for Storage, the external packing box comprising metered dose inhaler, specifically can refer to United States Patent (USP) US 6,119,853,6,179,118,6, 315,112,6,352,152,6,390,291 and 6,679,374 patents relevant with batching counter there are also but be not limited to, United States Patent (USP) US 6,360,739 and 6,431,168.

Medicinal aerosol can be used to manufacture conventional batch production method and equipment well known to those skilled in the art to carry out The large-scale production of wound packages medicine.Thus, for example metering valve is crimped in a kind of method for producing suspension aerosol in batches Empty cylinder is formed on one aluminium pot.Granulated drug is fitted into filling container, and suitable excipient and liquefied propellant are passed through Filling container pressurization is filled in manufacture container.Drug suspension is mixed before entering filling machine circulation, by aliquot Drug suspension be filled in cylinder by metering valve.In the embodiment of other batch production Liquid Aerosols, it will measure Valve, which is crimped on an aluminium pot, forms empty cylinder.The drug of dissolution is fitted into filling container, and by suitable excipient and liquefied Propellant is filled in manufacture container by filling container pressurization.

In process of production, the liquid preparation of every equal portions is added in open container at a temperature of cold enough, with true Protect preparation will not evaporation loss, after powder charge again by metering valve crimping to the container.

In general, the cylinder of each filling is examined, is weighed, stamps lot number, before release test in the producing by batch of drug It is fitted into disk and stores.Suspension and solution containing the compounds of this invention or its pharmaceutically acceptable salt can also be by spraying Device administers to a patient.Solvent or suspension for atomization are all pharmaceutically acceptable liquid, such as water, salting liquid, alcohol or two First alcohol, such as ethyl alcohol, isopropanol, glycerine, propylene glycol, polyethylene glycol or their mixture.Salt used in salting liquid be to There is no or has the salt of seldom pharmacological activity after medicine.Organic salt, such as alkali metal salt or ammonium halide salt, such as sodium chloride, potassium chloride Or organic salt, such as potassium, sodium and ammonium salt and organic acids such as ascorbic acid, citric acid, acetic acid, tartaric acid may be used to this mesh 's.

Other pharmaceutically acceptable excipient can also be used in suspension or solution.The compounds of this invention or its pharmaceutically The stability of acceptable salt, can be by being added inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid；Organic acid such as Vitamin C Acid, citric acid, acetic acid, tartaric acid etc., complexometric reagent such as EDTA or citric acid and its salt or antioxidant such as vitamin E and anti- Bad hematic acid.In the formulation, the above excipient can be used alone or together to stablize the compounds of this invention or its and can pharmaceutically connect The salt received.Preservative such as benzalkonium chloride, benzoic acid and its salt can also be added in preparation.Particularly, surface-active can be added Agent is used to improve the physical stability of suspending agent.Surfactant such as, lecithin, dioctyl sulfo-succinic acid disodium, oleic acid and Sorbitan ester.

Another aspect of the present invention relates to the dosage forms of intranasal administration.

The dosage form of intranasal administration includes that the pressurized aerosol formulation and aqueous solution preparation of nose are given by force (forcing) pump.It is non-pressurised And the preparation for being suitable for intranasal administration gains a special interest.For this purpose, suitable preparation is using water as diluent or load Body.The conventional excipients that the liquid dosage form of preparation lung or intranasal administration uses have buffer, tension regulator etc..Aqueous solution system Agent can also be by Neulized inhalation to intranasal administration.The compounds of this invention or its pharmaceutically acceptable salt can be configured to using stream The liquid preparation of body distributor transmitting administration, fluid distributor contains a distribution nozzle and aperture, when the power that user applies When being applied to the pump configuration of fluid distributor, the liquid preparation of dosing is distributed by distribution nozzle or dispensing aperture.This Kind fluid distributor is generally provided with the storage tank for accommodating multiple dosing liquid preparations, and dosage can pass through the movement point of continuously pump Match.Configurable distribution nozzle or aperture are used for liquid preparation spray distribution with being inserted into user nostril into nasal cavity.It is aforementioned to mention And fluid distributor be the type illustrated in patent WO05/044354, entire contents are incorporated in the present invention by reference.It should Distributor has the shell for accommodating fluid discharging apparatus, and fluid discharging apparatus includes on the container for being mounted on and accommodating liquid preparation Force (forcing) pump.Shell have at least one can finger manipulation side lever, which can move inward relative to shell, with cam band The dynamic intracorporal container of shell is upward, contracts so as to cause pump pressure the preparation of dosing pumping out pump rod by the nose nozzle of shell (stem).Especially preferred fluid distributor is the general type described in Figure 30-40 of patent WO05/044354.

It is suitable for the pharmaceutical composition of intranasal administration, carrier therein is solid, including partial size for example at 20-500 microns Corase meal；It can be administered in such a way, powder fills in a reservoir, holds close to nasal cavity, quick by nasal passage Sucking.Suitable composition, aqueous solution or oil solution comprising the compounds of this invention or its pharmaceutically acceptable salt, wherein carrying Body is liquid, is administered using nasal spray or is administered as nasal drop.

Being suitble to the pharmaceutical composition of percutaneous dosing can be used with isolated patch form, for close with the epidermis of patient Contact one section of longer time.See for example, discharge active component, common description from patch can be penetrated by ion Pharmaceutical Research,3(6),318(1986)。

Pharmaceutical composition suitable for local administration can also be configured to ointment, emulsion, suspension, washing lotion, pulvis, molten Liquid, paste, gelling agent, spray, aerosol or finish.Ointment, emulsion and gelling agent can be with water or oleaginous base plus conjunction Suitable thickener and/or gelling agent are prepared.Matrix such as atoleine, for example poly- second of vegetable oil such as peanut oil, castor oil or solvent Glycol.Thickener and gelling agent will be selected according to the property of matrix, include paraffin, aluminum stearate, hexadecanol and octadecyl alcolol Mixture, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivative and/or glycerin monostearate, and/ Or nonionic emulsifier.

Lotion can be prepared with water or oleaginous base, and typically contain one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickener.

External powder agent needs to be added suitable powdered substrate, such as talcum powder, lactose or starch when preparing.Dropping liquid is matched System generally uses water or non-aqueous base, additionally contains one or more dispersing agents, chaotropic agent, suspending agent or preservative.

The preparation of local application can daily to affected part in single or divided doses, skin affected part use impermeable plastic wound dressing.Even Continuous, long-term administration can be realized by pasting drug-reservoir.

The pharmaceutical composition for treating eye or other outside organizations such as mouth, skin can be with local application's cream and cream The form application of agent.When being configured to ointment, the compounds of this invention or its pharmaceutically acceptable salt can be using paraffin or can be with The miscible ointment bases of water.In addition, the compounds of this invention or its pharmaceutically acceptable salt can use oil-in-water or Water-In-Oil Substrate preparation at emulsion.

For parenteral pharmaceutical composition include water and non-aqueous sterile injection liquid, can containing antioxidant, Buffer, bacteriostatic agent and solute make the preparation and the isotonic and aqueous and anhydrous nothing of the blood of specified recipient Bacterium suspension can contain suspending agent and thickener.The composition can be such as close in unit dose or multi-dose container It stores, and can be stored in freeze-drying (freeze-drying) condition in the ampoule and medicine bottle of envelope, only need to add immediately using preceding Enter sterile liquid carrier, such as water for injection.Extemporaneous injection solutions and suspension can be by sterile powder, granula and tablet systems It is standby.

The compound of the present invention and pharmaceutical composition can be with one or more other therapeutic agents use in conjunction, the treatments Agent is selected from anti-inflammatory agent, anticholinergic drug (especially M₁/M₂/M₃Receptor antagonist), β₂3 adrenergic receptor agonists, anti-sense Stain, such as antibiotic or antivirotic or antihistamine.The present invention further provides a kind of compositions, and it includes a kind of formula (I) Shown compound or its pharmaceutically acceptable salt and one or more other active therapeutic agents, the active therapeutic agent are selected from Anti-inflammatory agent, such as steroidal anti-inflammatory drugs, non-steroid anti-inflammatory drug, anticholinergic drug, β₂3 adrenergic receptor agonists, anti-sense Stain such as antivirotic or antibacterial agent or antihistamine.Another aspect of the present invention relates to some compositions, and it includes formula (I) Shown compound or its pharmaceutically acceptable salt and β₂3 adrenergic receptor agonists, anticholinergic drug and/or PDE-4 Inhibitor and/or antihistamine.

In some embodiments, the present invention includes a kind of using the compounds of this invention safely, effectively measured or its pharmacy Upper acceptable salt and one or more active therapeutic agents, the method for the disease that treatment PI3K kinase activity disorder mediates.

Some specific compounds of the invention have the selectivity better than other PI3K kinases to PI3K δ kinases.Therefore, originally The another aspect of invention provides a kind of pharmaceutical composition, and it includes shown in the formula (I) for acting on PI3K δ kinases of selectivity The salt of compound or its pharmaceutical acceptable and other PI3K kinases are acted on, the chemical combination as shown in the formula (I) of PI3K γ kinases The salt of object or its pharmaceutical acceptable.

On the other hand, the present invention also includes composition, and it includes one or two kinds of other therapeutic agents.

To those skilled in the art, following situations is clear, it may be assumed that in appropriate circumstances, other therapeutic agents It can be the form such as alkali metal salt, ammonium salt of salt, or as the salt of sour addition or the form of the form of prodrug or ester Such as the form of lower alkyl esters or solvate for example optimizes activity and/stability and/or physical characteristic, as dissolubility, The hydrate of therapeutic component.Following situation is equally clearly that is, in appropriate circumstances, active therapeutic ingredient is with optics Pure form application.

In some embodiments, the present invention provides a kind of product, includes chemical combination shown in formula (I) as combination preparation Object and at least one other therapeutic agents, contained ingredient is simultaneously, respectively or be orderly used to treatment.In other embodiments In, what is treated is the treatment of the disease or illness that are mediated by PI3K kinase activity.Product as combination preparation includes group Object is closed, the composition contains formula (I) compound represented and other therapeutic agents of the present invention in identical pharmaceutical composition, Or containing individual formula (I) compound represented and other therapeutic agents of the present invention, such as in the form of medicine box.

In some embodiments, the present invention provides a kind of pharmaceutical composition, and it includes formula (I) compounds represented and its His therapeutic agent.Optionally, described pharmaceutical composition can also include above-described pharmaceutically acceptable carrier.

In some embodiments, the invention also includes a kind of medicine box, contain two or more individual pharmaceutical compositions Object, wherein at least one composition contain formula (I) compound represented of the present invention.In other embodiments, medicine box includes For storing the different utensils of the various pharmaceutical compositions, such as container, separated bottle or separated foil bag respectively. Such example is blister package.Commonly used in package troche, capsule etc..

Medicine box of the invention can be used for different dosage forms, such as orally and parenterally dosage form, for difference Spacing of doses applies individual composition, or is stepped up individual composition for another kind relatively.In order to increase compliance, Medicine box of the invention usually all contains operation instruction.

In combination therapy of the invention, the compounds of this invention and other therapeutic agents can be by identical or different factories Family's preparation is prepared.Moreover, the compounds of this invention and other therapeutic agents can be collectively incorporated into a therapeutic combination: (i) exists Combination product is issued to (ii) before (such as the medicine box containing the compounds of this invention and other therapeutic agents) doctor Before facing application, (iii) is carried out by doctor oneself (or under doctor's guidance) and is carried out by patient oneself, such as is successively being applied During the compounds of this invention and other treatment.

Correspondingly, the present invention provides compounds shown in formula (I) or its pharmaceutically acceptable salt is swashed in treatment by PI3K The purposes in disease or illness that enzymatic activity is mediated, drug therein are prepared for being co-administered with other therapeutic agents.This Invention additionally provides the purposes of the other therapeutic agents of disease or illness that treatment is mediated by PI3K kinase activity, wherein described Compound described in drug and formula (I) of the present invention is co-administered.

The present invention also provides formula (I) compounds represented for treating the disease or disease mediated by PI3K kinase activity The purposes of disease, wherein formula (I) compound represented and other therapeutic agents are prepared to the preparation for combined administration.The present invention is also Other therapeutic agents are provided for treating the purposes of the disease or illness that are mediated by PI3K kinase activity, wherein other described Therapeutic agent and formula (I) compound represented of the present invention are prepared to the preparation for combined administration.

The present invention also provides formula (I) compounds to treat the purposes in the disease or illness that PI3K kinase activity mediates, Wherein patient previously (such as in 24 hours) has been treated with other therapeutic agents.The present invention also provides other treatments Purposes of the agent in the treatment disease and illness that are mediated by PI3K kinase activity, wherein patient previous (such as in 24 hours) has been Through being treated with formula (I) compound represented.Formula (I) compound represented is auxiliary as unique active component or with other Agent or drug are used cooperatively, wherein adjuvant or drug such as immunosuppressor, immunomodulator or other anti-inflammatory agents, for treating Or prevent the drug or Chemo-Therapy of the acute or chronic rejection of of the same race or heterograft or inflammation or autoimmune disease Agent is treated, such as malignant cell antiproliferative.For example, formula (I) compound represented of the present invention and neural pherylarsin oxide It is co-administered, for example, cyclosporin A or FK506；MTOR inhibitors, such as rapamycin, 40-O- (2- ethoxy)-Lei Pa are mould Element, CCI779, ABT578, AP23573, TAFA-93 etc., biolimus-7 or biolimus-9, ascosin have immune suppression Make active ABT-281, ASM981, cortin, cyclophosphamide, azathioprene, methotrexate, leflunomide, imidazoles Vertical guest, mycophenolic acid or its salt, mycophenolate, 15-deoxyspergualine or immunosuppressive homologue, analog or derivative Object, pkc inhibitor etc., as described in patent WO 02/38561or WO 03/82859, embodiment compound 56 or 70, or JAK3 kinase inhibitor, such as: N- benzyl -3- benzal-Isosorbide-5-Nitrae-dihydroxy cyanoacetamide-alpha-cyano-(3,4- dihydroxy)-N- Benzyl cinnamamide (tyrphostin AG 490), prodigiosin 25-C (PNU156804), 4- (4 '-hydroxy benzenes Base)-amido-6,7-dimethoxy quinazoline (WHI-P131), [4- (the bromo- 4- hydroxy phenyl of 3-)-amino -6,7- dimethoxy Quinazoline] (WHI-P154), 4- (3 ', 5 '-two bromo- 4 '-hydroxy phenyl)-amido-6,7-dimethoxy quinazoline WHI-P97, KRX-211,3- { (3R, 4R) -4- methyl -3- [methyl-(7H- pyrrolo- [2,3-d] pyrimidine-4-yl)-amino]-piperidines -1- Base } -3- oxo-propionitrile, the form presence of free form or pharmaceutically acceptable salt, such as list citric acid (also referred to as CP-690, 550) or the compound in patent WO 04/052359 or WO 05/066156, immunosuppressor monoclonal antibody, leucocyte by The monoclonal antibody of body, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their ligand, and other immunomodulatory compounds, have CTLA4 extracellular domain or its mutant at least The recombination binding molecule of a part, for example, the CTLA4lg (such as referred to as ATCC 68629) that connect with non-CTLA4 protein sequence or Its variant (for example, LEA29Y) or other adhesion molecule inhibitors such as LFA-1 antagonist ICAM-1 or -3 antagonist, VCAM-4 are short of money Anti-agent or VLA-4 antagonist or antihistamine or pectoral, bronchodilator, angiotensin receptor blocker or anti-sense Stain.

Compound shown in formula (I) of the present invention and other immunosuppressor/immunomodulators, anti-inflammatory agent, chemotherapeutant Or anti-infective co-administration, wherein immunosuppressor/immunomodulator, anti-inflammatory agent, chemotherapeutant or anti-infective are common The dosage of medication depends on the type of drug combination, is steroid compound or calcineurin inhibitors, and be used for The specific drug for the treatment of and treatment condition etc..

In one embodiment, the present invention includes containing formula (I) compound or its pharmaceutically acceptable salt and β₂Kidney The combination of upper parathyrine receptor stimulating agent.

β₂The example of adrenoceptor agonists includes that (it can be racemic chemical combination to salmeterol (salmeterol) Object or single enantiomter, such as R- enantiomter), salbutamol (salbutamol) (its can for racemic compound or Single enantiomter, such as R- enantiomter), (it can be racemic compound or single to Formoterol (formoterol) Diastereoisomer, such as R, R- diastereoisomer), salmefamol (salmefamol), fenoterol (fenoterol), card Mo Teluo (carmoterol), Yi Tanteluo (etanterol), naminterol (naminterol), Clenbuterol (clenbuterol), pirbuterol (pirbuterol), Flerobuterol (flerbuterol), Reproterol (reproterol), bambuterol (bambuterol), datro (indacaterol), Terbutaline (terbutaline) And their salt, such as the sulfate or free of the xinafoate (1- hydroxy-2-naphthoic acid salt) of salmeterol, salbutamol The fumarate of alkali or Formoterol.In some embodiments, long-acting beta₂Adrenoceptor agonists, for example, mentioning It is preferred for effective bronchiectasis up to 12 hours or the compound of longer time.

β₂Adrenoceptor agonists can be with the form of pharmaceutically acceptable sour forming salt.It is described pharmaceutically The acid of receiving is selected from sulfuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (such as 1- or 3- hydroxy-2-naphthoic acid), cinnamic acid, substituted meat Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3- (1- naphthalene) acrylic acid, benzoic acid, 4- methoxy benzoic acid, 2- or 4-HBA, 4- chlorobenzoic acid and 4- Phenylbenzoic acid.

Suitable anti-inflammatory agent includes corticosteroid.It can be used for and formula (I) compound or its pharmaceutically acceptable salt group The suitable corticosteroid closed is those oral and sucking corticosteroids, and its prodrug with anti-inflammatory activity.Example Including methylprednisolone, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-[(4- methyl-1,3-thiazole - 5- carbonyl) oxygroup] -3- oxo-androst-Isosorbide-5-Nitrae--17 β of diene-thiocarboxylic acid S- fluorine methyl esters, fluoro- 17 α-[(the 2- furan of 6 α, 9 α-two Mutter carbonyl) oxygroup]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- fluorine methyl esters (furancarboxylic acid Fluticasone), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--17 α of methyl -3- oxo-propionyloxy-androsta--17 β of Isosorbide-5-Nitrae-diene - Thiocarboxylic acid S- (2- oXo-tetrahydro furans -3S- base) ester, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--17 α of methyl -3- oxo - (2,2,3,3- tetramethyl cyclopropyl carbonyl) oxygroup--17 β of androstane -1,4- diene-thiocarboxylic acid S- cyano methyl ester and 6 α, 9 α-two Fluoro- -17 β of -17 α of -16 Alpha-Methyl of 11 beta-hydroxy-(1- ethyl cyclopropyl carbonyl) oxygroup -3- oxo-androst -1,4- diene-is thio Carboxylic acid S- methyl fluoride ester, beclomethasone ester (such as 17- propionic ester or 17,21- dipropionic acid rouge), budesonide (budesonide), Flunisolide (flunisolide), Mometasone ester (such as momestasone furoate), Triamcinolone acetonide (triamcinolone Acetonide), sieve fluoronaphthalene moral (rofleponide), ([[(R)-cyclohexyl is sub- by 16 α, 17- for ciclesonide (ciclesonide) Methyl] bis- (oxygroups)] -11 β, pregnant steroid-Isosorbide-5-Nitrae-diene -3, the 20- diketone of 21- dihydroxy -), butixocort propionate (butixocort Propionate), RPR-106541 and ST-126.Preferred corticosteroid includes fluticasone propionate (fluticasone Propionate), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-methyl-17-alpha-[(4- methyl-1,3- thiazole -5- carbonyl) oxygroup] - 3- oxo-androst-Isosorbide-5-Nitrae--17 β of diene-thiocarboxylic acid S- methyl fluoride ester, fluoro- 17 α-of 6 α, 9 α-two [(2- furanylcarbonyl) oxygen Base]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- methyl fluoride ester, 6 α, 9 α-two are fluoro- - 17 α of -16 Alpha-Methyl -3- oxo of 11 beta-hydroxy-(2,2,3,3- tetramethyl cyclopropyl carbonyl) oxygroup-androstane -1,4- diene -17 - 17 α of β-thiocarboxylic acid S- cyano methyl ester and -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-(1- methylcyclopropyl groups carbonyl) oxygen - 17 β of base -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters.In some embodiments, corticosteroid is 6 α, - 16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of fluoro- 17 α-of 9 α-two [(2- furanylcarbonyl) oxygroup]-11 beta-hydroxy-sulphur For carboxylic acid S- methyl fluoride ester.

To Transcription inhibition with selectivity (compared with transcriptional activation), can be used for combination therapy with glucocorticoid swash Moving active nonsteroidal compound includes the compound that those covered in following patent: WO03/082827, WO98/ 54159、WO04/005229、WO04/009017、WO04/018429、WO03/104195、WO03/082787、WO03/ 082280、WO03/059899、WO03/101932、WO02/02565、WO01/16128、WO00/66590、WO03/086294、 WO04/026248, WO03/061651 and WO03/08277.More nonsteroidal compounds are in WO2006/000401, WO2006/ It is included in 000398 and WO2006/015870.

The example of anti-inflammatory agent includes nonsteroidal anti-inflammatory drug (NSAID ' s).

The example of NSAID ' s includes nasmil, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (such as theophylline, PDE4 inhibitor or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene close At inhibitor (such as montelukast), iNOS inhibitor, trypsase and elastatinal, Beta 2 integrin antagonist With adenosine receptor agonist or antagonist (e.g., adenosine 2a receptor stimulating agent), (such as chemokine receptors is short of money for cytokine antagonist Anti-agent, including CCR3 antagonist), cytokine synthesis inhibitor or 5-LO inhibitor.Wherein, iNOS (inductivity one Nitric oxide synthase) inhibitor is preferably administered orally.The example of iNOS inhibitor includes those in WO93/13055, WO98/ 30537, compound disclosed in WO02/50021, WO95/34534 and WO99/62875.CCR3 inhibitor include those Compound disclosed in WO02/26722.

In one embodiment, the present invention provides formula (I) compound in the group with phosphodiesterase 4 (PDE4) inhibitor Application in conjunction, the especially application in the case where being suitable for sucking preparation.PDE4 specificity for this aspect of the present invention Inhibitor can be known inhibition PDE4 enzyme or be found any compound as PDE4 inhibitor, they are only PDE4 Inhibitor is not to inhibit other members in PDE family, such as the compound of PDE3 and PDE5.Compound includes cis- -4- cyano - 4- (3- cyclopentyloxy -4- methoxyphenyl) hexamethylene -1- carboxylic acid, 2- carbomethoxy -4- cyano -4- (3- cyclo propyl methoxy - 4- difluoro-methoxy phenyl) hexamethylene -1- ketone and cis--[4- cyano -4- (3- cyclo propyl methoxy -4- difluoromethoxy phenyl Base) hexamethylene -1- alcohol]；It also include cis- -4- cyano -4- [3- (cyclopropyl oxygroup) -4- methoxyphenyl] hexamethylene -1- carboxylic acid (also referred to as Xi Luosi) and its salt, ester, prodrug or physical form, in 09 month 1996 No. 03 United States Patent (USP) US 5 authorized, It is disclosed in 552,438, this patent and its disclosed compound by reference and are integrally incorporated in the present invention.

The example of anticholinergic agent is compounds that those are used as muscarinic receptor antagonist, especially those as M1 or M3 receptor antagonist, M₁/M₃Or M₂/M₃Receptor dual antagonist or M₁/M₂/M₃The compound of the general antagonist of receptor.Inhalation Example compound include ipratropium (for example, as bromide, CAS 22254-24-6, with() be Trade name is sold), oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium (for example, as bromide, CAS 136310-93-5, with() sold for trade name)；Be also interested in there are also Revatropate (for example, As hydrobromate, CAS 262586-79-8) and the LAS-34273 disclosed in WO01/04118.What is be administered orally is instantiating Closing object includes pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4 or its hydrobromate CAS 133099-07-7 is sold by trade name of Enablex), oxybutynin (CAS 5633-20-5, with() Sold for trade name), terodiline (CAS 15793-40-5), Tolterodine (CAS 124937-51-5 or its tartrate CAS 124937-52-6, with() sold for trade name), Austria for ammonium (for example, as bromide, CAS 26095- 59-0, withSold for trade name), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478- 37-1 or its succinate CAS 242478-38-2, i.e. compound YM-905, with() sold for trade name It sells).

In some embodiments, the present invention provides one kind to include formula (I) compound or its pharmaceutically acceptable salt, with The combination of H1 antagonist.The example of H1 antagonist includes, but are not limited to Amlexanox (amelexanox), this western imidazoles (astemizole), azatadine (azatadine), azelastine (azelastine), Acrivastine (acrivastine), Brompheniramine (brompheniramine), cetirizine (cetirizine), levocetirizine (levocetirizine), second Fluorine benefit piperazine (efletirizine), chloropheniramine (chlorpheniramine), clemastine (clemastine), marezine (cyclizine), Carebastine (carebastine), cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), diformazan indenes (dimethindene), Ebastine (ebastine), epinastine (epinastine), second Fluorine benefit piperazine (efletirizine), fexofenadine (fexofenadine), hydroxyzine (hydroxyzine), Ketotifen (ketotifen), Loratadine (loratadine), levocabastine (levocabastine), Mizolastine (mizolastine), mequitazine (mequitazine), Mianserin (mianserin), the primary sting of promise (noberastine), meclizine (meclizine), Tecastemizole (norastemizole), olopatadine (olopatadine), piperacetazine (picumast), than Lamine (pyrilamine), phenergan (promethazine) is special Fei Nading (terfenadine), Tripelennamine (tripelennamine), temelastine (temelastine), nedeltran (trimeprazine) and triprolidine (triprolidine), preferred cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine) and fexofenadine (fexofenadine).At another In embodiment, the present invention provides one kind include formula (I) compound or its pharmaceutically acceptable salt, with H3 antagonist (and/ Or inverse agonist) combination.The example of H3 antagonist includes that those are disclosed in WO2004/035556 and WO2006/045416 Compound.Other histamine receptor antagonists that can be used for combining with the compound of the present invention include H4 receptor antagonist (and/or Inverse agonist), such as the chemical combination disclosed in Jablonowski et al., J.Med.Chem., 2003,46,3957-3960 Object.

Therefore, another aspect, the present invention provide one kind and include formula (I) compound or its pharmaceutically acceptable salt, with The combination of PDE-4 inhibitor.

Therefore, on the other hand, it includes formula (I) compound or its pharmaceutically acceptable salt that the present invention, which provides a kind of, with β₂- The combination of adrenoceptor agonists.

Therefore, on the other hand, the present invention provides a kind of compound or its pharmaceutically acceptable salt including formula (I), with The combination of corticosteroid.

Therefore, on the other hand, the compound or its pharmaceutically acceptable salt the present invention provides one kind including formula (I), With the combination of nonsteroidal GR agonist.

Therefore, on the other hand, the compound or its pharmaceutically acceptable salt the present invention provides one kind including formula (I), With the combination of anticholinergic drug.

Therefore, on the other hand, the compound or its pharmaceutically acceptable salt the present invention provides one kind including formula (I), With antihistaminic combination.

Therefore, on the other hand, the compound or its pharmaceutically acceptable salt the present invention provides one kind including formula (I), With PDE4 inhibitor and β₂The combination of adrenoceptor agonists.

Therefore, on the other hand, the compound or its pharmaceutically acceptable salt the present invention provides one kind including formula (I), With the combination of anticholinergic drug and PDE-4 inhibitor.

Therefore, including defined above group combination of the above is prepared into pharmaceutical composition and comes using in which can be convenient It closes and represents another aspect of the present invention with the pharmaceutical composition of pharmaceutically acceptable diluent or carrier.

The single compound of these combinations can give with alone or in combination pharmaceutical preparation form order of administration or simultaneously Medicine.In some embodiments, single compound component is administered simultaneously with combined pharmaceutical preparation form.Known treatment agent Suitable dosage be easy to be understood by the person skilled in the art.

Therefore, on the other hand, it includes formula (I) compound or its pharmaceutically acceptable salt that the present invention, which provides a kind of, with it The pharmaceutical composition of his therapeutically active agent combination.

Therefore, another aspect, the present invention provide one kind and include formula (I) compound or its pharmaceutically acceptable salt, with The pharmaceutical composition of PDE4 inhibitor combination.

Therefore, on the other hand, it includes formula (I) compound or its pharmaceutically acceptable salt that the present invention, which provides a kind of, with β 2- The pharmaceutical composition of adrenoceptor agonists combination.

Therefore, on the other hand, it includes formula (I) compound or its pharmaceutically acceptable salt that the present invention, which provides a kind of, with skin The pharmaceutical composition of matter steroid combination.

Therefore, on the other hand, it includes formula (I) compound or its pharmaceutically acceptable salt that the present invention, which provides a kind of, and non- The pharmaceutical composition of steroid GR agonist combinations.

Therefore, on the other hand, it includes formula (I) compound or its pharmaceutically acceptable salt that the present invention, which provides a kind of, and anti- The pharmaceutical composition of cholinergic agent combination.

Therefore, on the other hand, it includes formula (I) compound or its pharmaceutically acceptable salt that the present invention, which provides a kind of, and anti- The pharmaceutical composition of histamine drug combination.

Therefore, another aspect, the present invention provide one kind and include formula (I) compound or its pharmaceutically acceptable salt, with The pharmaceutical composition of PDE4 inhibitor and beta-2-adrenoreceptor agonists combination.

Therefore, on the other hand, it includes formula (I) compound or its pharmaceutically acceptable salt that the present invention, which provides a kind of, and anti- The pharmaceutical composition of cholinergic agent and the combination of PDE4 inhibitor.

Formula (I) compound can also be advantageously utilised in the combination with other compounds, or and other therapeutic agents, it is especially anti- In the combination of multiplication agent.Such antiproliferative includes, but are not limited to aromatase inhibitor；Antiestrogenic；Topoisomerase I Inhibitor；Topoisomerase II inhibitors；Microtubule active agent；Alkylating agent；Histon deacetylase (HDAC) inhibitor；Inducing cell point The compound of change process；Cyclooxygenase-2 inhibitors；MMP inhibitor；MTOR inhibitors；Antitumor antimetabolite；Platinum compounds；Target To/reduce the compound of albumen or lipid kinase activity and the compound of other anti-angiogenesis；Targeting reduces or inhibits albumen Or the compound of lipid phosphate esterase active；Gonadorelin excitomotor；Antiandrogen；Methionine aminopeptidase inhibitor；Double phosphines Hydrochlorate；Biological response modifiers；Antiproliferation antibodies；Heparanase inhibitors；The carcinogenic hypotype inhibitor of Ras；Telomerase inhibits Agent；Proteasome inhibitor；The medicament for treating neoplastic hematologic disorder；Targeting reduces or inhibits the active compound of Flt-3；Hsp90 suppression Preparation；Temozolomide ()；And Calciumlevofolinate.

Term used herein " aromatase inhibitor " refers to that the compound inhibited estrogen production, i.e. inhibition substrate are male Alkene diketone and testosterone are converted to the compound of oestrone and estradiol respectively.The term includes, but are not limited to: steroid, especially It is atamestane (atamestane), Exemestane (exemestane) and formestane (formestane)；And especially Non-steroids, especially aminoglutethimide (aminoglutethimide), Rogletimide (roglethimide), pyrrole Rumi Spy (pyridoglutethimide), Trilostane (trilostane), Testolactone (testolactone), ketoconazole (ketoconazole), fluorine chlorazol (vorozole), Fadrozole (fadrozole), Anastrozole (anastrozole) and come it is bent Azoles (letrozole).Exemestane can be with commercially available, such as the form administration that trade mark is Arnold new (AROMASIN).Formestane (formestane) can be with commercially available, the form if trade mark is Lentaron (LENTARON) is administered.Fadrozole (fadrozole) Can be with commercially available, the form if trade mark is AFEMA is administered.Anastrozole (anastrozole) can be with commercially available, such as trade mark It is administered for the form of Arimidex (ARIMIDEX).Letrozole (letrozole) can be with commercially available, if trade mark is fluon (FEMARA) or the form of FEMAR is administered.Aminoglutethimide (aminoglutethimide) can be with commercially available, if trade mark is Austria The form administration of U.S. fixed (ORIMETEN).The present invention include aromatase inhibitor chemotherapeutic combination be particularly useful for the treatment of hormone by The tumour that body is positive, such as tumor of breast.

Term used herein " antiestrogenic ", refers to the compound in Estrogen Receptor antagonising oestrogen effectiveness. The term includes, but are not limited to tamoxifen (tamoxifen), fulvestrant (fulvestrant), Raloxifene (raloxifene) and raloxifene hydrochloride (raloxifene hydrochloride).Tamoxifen (tamoxifen) can With with commercially available, the form if trade mark is Nolvadex/Nolvadex-D (NOLVADEX) is administered.Raloxifene hydrochloride (raloxifene Hydrochloride) can be with commercially available, the form if trade mark is Yi Weite (EVISTA) is administered.Fulvestrant It (fulvestrant) can be with dosage form disclosed in United States Patent (USP) US 4,659,516 or commercially available, as trade mark is The form of FASLODEX is administered.The present invention includes that the combination of antiestrogenic chemotherapeutic is particularly useful for the treatment of estrogen receptor and is positive Tumour, such as tumor of breast.

Term used herein " antiandrogen " refers to any substance that can inhibit male sex hormone biological action, it is wrapped Include, but be not limited to, Bicalutamide (bicalutamide, trade name CASODEX), dosage form can according to United States Patent (USP) US 4, 636,505 prepare.

Term used herein " Gonadorelin excitomotor " includes, but are not limited to abarelix (abarelix), Ge She Rayleigh (goserelin) and goserelin acetate.Goserelin is disclosed in United States Patent (USP) US 4,100,274, can be with city It sells, the form if trade mark is Zoladex (ZOLADEX) is administered.Abarelix (abarelix) can be according to United States Patent (USP) US Method disclosed in 5,843,901 prepares dosage form.

Term used herein " topoisomerase I inhibitor " includes, but are not limited to topotecan (topotecan), lucky Horse replaces health (gimatecan), Irinotecan (irinotecan), camptothecine (camptothecian) and the like, 9- nitro Camptothecine (9-nitrocamptothecin) and macromolecular camptothecin conjugated compound PNU-166148 are (in WO 99/17804 Compound A1).Irinotecan can be with commercially available, and the form if trade mark is Cape Extension (CAMPTOSAR) is administered.Topotecan can Be administered with the form of U.S. new (HYCAMTIN) such as trade mark with commercially available.

Term used herein " Topoisomerase II inhibitors " includes, but are not limited to anthracycline compound, such as how soft ratio Star (doxorubicin), its Lipidosome, the triumphant Lay of trade name (CAELYX)；Daunomycin (daunorubicin)；Table It is soft than star (epirubicin)；Idarubicin (idarubicin)；The not soft pyrrole star (nemorubicin) of naphthalene；Anthraquinones rice support anthracene Quinone (mitoxantrone) and Losoxantrone (losoxantrone)；Podophillotoxines etoposide (etoposide) and replace Buddhist nun It moors glycosides (teniposide).Etoposide can be with commercially available, and the form if trade mark is Etopophos (ETOPOPHOS) is administered.It replaces Buddhist nun moors glycosides can be with commercially available, and the form if trade mark is VM 26-BRISTOL is administered.Doxorubicin can be with commercially available, such as quotient It is designated as the form administration of adriamycin (ADRIBLASTIN) or adriamycin (ADRIAMYCIN).Epirubicin can be with city It sells, the form if trade mark is Pharmorubicin RD (PHARMORUBICIN) is administered.Idarubicin can be with commercially available, as trade mark does good Only it is administered up to the form of (ZAVEDOS).Mitoxantrone can be with commercially available, such as the form that trade mark is can destroy tumors (NOVANTRON) Administration.

Term " microtubule active agent " refers to microtubule stabilizer, microwave destabiliser and microtubule polymerization inhibitor.It includes, but not It is limited to taxanes, such as taxol (paclitaxel) and Docetaxel (docetaxel)；Vinca alkaloids, such as Changchun Alkali (vinblastine), especially vinblastine sulfate, vincristine, especially vincristine sulphate and vinorelbine (vinorelbine)；discodermolides；Colchicin；And Epothilones and its derivative, such as epothilone B or D Or derivatives thereof.Taxol can be with commercially available, and the form if trade mark is taxol (TAXOL) is administered.Docetaxel can be with It is commercially available, if trade mark is that safe Supreme Being is plain (TAXOTERE).Vinblastine sulfate can be with commercially available, if trade mark is VINBLASTIN R.P. form administration.Vincristine sulphate can be with commercially available, and the form if trade mark is FARMISTIN is administered. Discodermolide can be obtained according to method disclosed in United States Patent (USP) US 5,010,099.It further include in WO 98/ 10121, United States Patent (USP) US6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO Epothilones analog derivative disclosed in 00/31247, particularly preferred ebomycin A and/or B.

Term used herein " alkylating agent " includes, but are not limited to cyclophosphamide (cyclophosphamide), different ring phosphorus Amide (ifosfamide), melphalan (melphalan) or Nitrosourea (nitrosourea, such as BCNU or carmustine).Ring phosphinylidyne Amine can be with commercially available, and the form if trade mark is cyclophosphamide (CYCLOSTIN) is administered.Ifosfamide can be with commercially available, such as Trade mark is that the form of Holoxan (HOLOXAN) is administered.

Term " histon deacetylase (HDAC) inhibitor " or " hdac inhibitor " refer to inhibition of histone deacetylase, and Compound with antiproliferative activity.It is included in compound disclosed in WO 02/22577, especially N- hydroxyl -3- [4- [[(2- ethoxy) [2- (1H- indol-3-yl) ethyl]-amino] methyl] phenyl] -2E-2- acrylamide, N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- base)-ethyl]-amino] methyl] phenyl] it -2E-2- acrylamide and its can pharmaceutically connect The salt received.Especially include Vorinostat (SAHA).

Term " antitumor antimetabolite " includes, but are not limited to 5-fluor-uracil (5-fluorouracil) or 5-FU； Capecitabine (capecitabine)；Gemcitabine (gemcitabine)；DNA demethylation reagent, such as U-18496 (5- ) and Decitabine (decitabine) azacytidine；Methotrexate (MTX) (methotrexate) and Edatrexate (edatrexate)；And antifol, such as pemetrexed (pemetrexed).Capecitabine can be with commercially available, such as quotient It is designated as the form administration of Xeloda (XELODA).Gemcitabine can be with commercially available, such as the form that trade mark is gemzar (GEMZAR) Administration.This term further includes monoclonal antibody Herceptin (trastuzumab), can be with commercially available, if trade mark is He Sai The form in spit of fland (HERCEPTIN) is administered.

Term used herein " platinum compounds " includes, but are not limited to carboplatin (carboplatin), cDDP (cis- Platin), cis-platinum (cisplatinum) and oxaliplatin (oxaliplatin).Carboplatin can be with commercially available, as trade mark isForm administration.Oxaliplatin can be with commercially available, and the form if trade mark is Le Satin (ELOXATIN) is given Medicine.

Term used herein " targeting/reduction albumen or lipid kinase activity or albumen or lipid phosphatase activeization Close the compound of object or other anti-angiogenesis " include, but are not limited to protein tyrosine kinase and/or serine and/or Threonine inhibitor or lipid kinase inhibitors, such as

A) it targets, reduces or inhibit platelet derived growth factor receptor (PDGFR) active compound；Targeting reduces Or inhibit the active compound of PDGFR, the compound of especially inhibition pdgf receptor includes N- phenyl-2-pyrimidine-amine derivatives, Such as Imatinib (imatinib), SU101, SU6668, GFB-111 etc.；

B) target, reduce or inhibit fibroblast growth factor acceptor (FGFR) active compound；

C) target, reduce or inhibit insulin-like growth factor receptor -1 (IGF-1R) active compound；Targeting reduces Or inhibiting the active compound of IGF-1R, the compound of especially inhibition IGF-1 receptor active includes those in patent WO 02/ Compound disclosed in 092599；

D) targeting, reduction or the compound for inhibiting Trk receptor tyrosine kinase family active；

E) targeting, reduction or the compound for inhibiting Axl Receptor Tyrosine Kinase family active；

F) targeting, reduction or the compound for inhibiting c-Met receptor active；

G) targeting, reduction or the compound for inhibiting Kit/SCFR receptor tyrosine kinase activity；

H) target, reduce or inhibit C-kit receptor tyrosine kinase (a part in PDGFR family) active chemical combination Object；Targeting, the compound for reducing or inhibiting C-kit receptor tyrosine kinase family active, especially inhibit the change of c-Kit receptor Close object, including Imatinib (imatinib) etc.；

I) it targets, reduce or inhibit c-Abl family and their gene fusion products, such as the change of BCR-Abl kinase activity Close object；Targeting, the compound for reducing or inhibiting c-Abl family member and their gene fusions include N- phenyl -2- pyrimidine - Amine derivative, such as Imatinib, PD180970, AG957, NSC 680410, from the PD173955 of ParkeDavis

J) it targets, Raf family member in reduction or inhibition protein kinase C (PKC) and serine/threonine kinases, MEK, SRC, JAK, FAK, PDK and Ras/MAPK family member, Pl (3) kinase families member or Pl (3) kinases associated kinase family at The compound of member and/or cell cycle protein dependent kinase family (CDK) member activity；Especially those are in United States Patent (USP) Staurosporine derivatives disclosed in US 5,093,330, such as midostaurin (midostaurin)；More examples of compounds It further include UCN-01；Safingol (safingol)；BAY 43-9006；Bryostatin 1；Piperazine Li Fuxin (Perifosine)；She Mo Fuxin (llmofosine)；RO 318220 and RO 320432；GO 6976；Isis 3521；LY333531/LY379196； Isoquinoline compound, such as in WO 00/09495 those disclosed；FTIs；PD184352；Or a kind of QAN697 (P13K suppression Preparation)；

K) target, reduce or inhibit the active compound of protein tyrosine kinase inhibitor；Targeting reduces or inhibits The active compound of protein tyrosine kinase inhibitor includes Gleevec (GLEEVEC) or tyrosine phosphorylation suppression Preparation；The preferred low molecular weight of tyrphostin (Mr < 1500) compound or its pharmaceutically acceptable salt, especially Compound selected from the third two eyeball class of two eyeball class of benzyl allyl or S- aryl sheet or Double bottom object quinolines, is further selected from tyrosine phosphorus Acidification inhibitors A23/RG-50810, AG 99, tyrphostin AG213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44 (+) Enantiomer, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG957 and Adaphostin (4- { [(2,5- dihydroxy phenyl) methyl] amino }-benzoic acid Buddha's warrior attendant alkyl ester, NSC 680410, adaphostin)；With

I) target, reduce or inhibit receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, The equal or heterodimer of ErbB3, ErbB4) active compound；Targeting reduces or inhibits Epidermal Growth Factor Receptor Family Compound refer in particular to inhibit EGF receptor family member (such as EGF receptor, ErbB2, ErbB3, ErbB4, or can with EGF or The substance that EGF associated ligands combine) compound, albumen or antibody, is especially summarized in the following documents or it is specific openly Compound, albumen or monoclonal antibody: WO 97/02266 (such as embodiment 39), EP 0564409, WO 99/03854, EP 0520722、EP 0566226、EP 0787722、EP 0837063、US 5,747,498、WO 98/10767、WO 97/ 30034, WO 97/49688 and WO 97/38983, WO 96/30347 (such as CP 358774), 96/33980 (such as compound of WO ZD 1839), WO 95/03283 (such as compound ZM105180), Herceptin (Trastuzumab), Cetuximab, Iressa, Erlotinib, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, E7.6.3, and 7H- pyrrolo- [2, the 3-d] pyrimidine derivatives being disclosed in WO 03/013541.

In addition, anti-angiogenic compounds include having other active mechanisms (for example, inhibiting not with albumen or lipid kinase It is related) compound, such as Thalidomide (THALOMID) and TNP-470.

The compound of targeting, reduction or inhibition albumen or lipid kinase activity is -1 inhibitor of phosphatase, phosphatase 2A suppression Preparation, PTEN inhibitor or CDC25 inhibitor, such as okadaic acid or derivatives thereof.

The compound of Cell differentiation inducing activity process is vitamin A acid, α-, γ-or Delta-Tocopherol, α-, γ-or δ-fertility triolefin Phenol.

Term used herein " cyclooxygenase-2 inhibitors " includes, but are not limited to Cox-2 inhibitor, and 5- is alkyl-substituted 2- fragrant amino phenylacetic acid and its derivative, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib is examined with cutting down Former times or 5- alkyl -2- fragrant amino phenylacetic acid, such as 5- methyl -2- (2 '-chloro- 6 '-fluoroanilino) phenylacetic acid or Lu meter Kao former times

Term used herein " diphosphonate " includes, but are not limited to Etidronic Acid, Clodronate, Tiludronic Acid, pa rice phosphine Acid, alendronic acid, ibandronic acid, Risedronic Acid and zoledronic acid.Etidronic Acid can with commercially available, as trade name Supreme Being sieve how (DIDRONEL) form administration.Clodronate can be with commercially available, as the form of trade name Bonefos (BONEFOS) is administered.It replaces Shandong phosphonic acids can be with commercially available, as the form of trade name SKELID is administered；Pamidronic acid (Pamidronic acid) can be with It is commercially available, such as trade name Aredia (AREDIA^TM) form administration；Alendronic acid can be with commercially available, such as trade name good fortune The form administration of kind beauty (FOSAMAX)；Ibandronic acid can be with commercially available, such as the shape of trade name Bang Luoli (BONDRANAT) Formula administration；Risedronic Acid can be with commercially available, as the form of trade name ANTU good (ACTONEL) is administered；Zoledronic acid can be with With commercially available, such as the form administration in trade name pool safe (ZOMETA).

Term " mTOR inhibitors ", which refers to, inhibits mammal rapamycin (mTOR) target protein, with antiproliferative activity Compound, such as sirolimus (sirolimus,), everolimus (Certican^TM), CCI-779 and ABT578.

Term used herein " heparanase inhibitors " refers to, targets, reduces or inhibit acetylsulfuric acid depolymerized heparin Compound.This term includes, but unlimited PI-88.

Term used herein " biological response modifiers " refers to lymphokine or interferon, such as interferon gamma.

Term used herein " the carcinogenic hypotype of Ras (such as H-Ras, K-Ras or N-Ras) inhibitor " refers to targeting, reduces Or inhibit the compound of Ras carcinogenic activity, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra)。

Term used herein " telomerase inhibitor " refers to the compound targeted, lowered or inhibited telomerase activity.Target To, reduce or inhibit the compound of telomerase activation to refer in particular to inhibit the compound of telornerase receptor, such as telomere mycin.

Term used herein " methionine aminopeptidase inhibitor " refers to targeting, reduction or inhibits methionine aminopeptidase activity Compound.Targeting, reduction or the inhibition active compound of methionine aminopeptidase include bengamide or derivatives thereof.

Term used herein " proteasome inhibitor " refers to targeting, reduction or the active chemical combination of protease inhibition body Object.Targeting, reduction or the active compound of protease inhibition body include PS-341 and MLN 341.

Term used herein " Matrix Metalloproteinase Inhibitors " or " MMP inhibitor " include, but are not limited to glue Former albumen peptides and non-peptide inhibitor, tetracycline derivant, such as hydroxamic acid peptide inhibitor Batimastat (batimastat) With its equivalent homologue Marimastat (marimastat, BB-2516) of oral bio, prinomastat (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996。

Term used herein " for treating the reagent of neoplastic hematologic disorder " includes, but are not limited to FMS- sample tyrosine kinase Inhibitor.Targeting reduces or inhibits FMS- sample tyrosine kinase receptor (Flt-3R) active compound；Interferon, 1-b-D- Arabinofuranosyl adenin cytimidine (ara-c) and bisulfan；With ALK inhibitor, such as targeting reduces or inhibits anaplastic lymphoma kinase Compound.

Targeting, reduce or inhibit FMS- sample tyrosine kinase receptor (Flt-3R) compound especially inhibit Flt-3 by The compound of body kinase families member, albumen or antibody, such as PKC412, midostaurin (midostaurin), staurosporin Derivative, SU11248 and MLN518.

The endogenous that term used herein " HSP90 inhibitor " includes, but are not limited to targeting, reduces or inhibit HSP90 The compound of atpase activity；Pass through the degradation of ubiquitin protein body enzymatic pathway, targeting, the chemical combination for reducing or inhibiting HSP90 client protein Object.Targeting, the Endogenous ATP for reducing or the compound of the Endogenous ATP enzymatic activity of HSP90 being inhibited to refer in particular to inhibit HSP90 The compound of enzymatic activity, albumen or antibody, for example, 17- allyl amino, 17-AAG (17AAG), The relevant compound of his geldanamycin, red shell rhzomorph and hdac inhibitor.

Term used herein " antiproliferation antibodies " includes, but are not limited to Herceptin (Herceptin^TM), toltrazuril Monoclonal antibody-DM1, Tarceva (Tarceva^TM), bevacizumab (Avastin^TM), Rituximab (), PR064553 (anti-CD40) and 2C4 antibody.Antibody means complete monoclonal antibody, polyclonal antibody, by the complete antibody of at least two The multi-specificity antibody and antibody fragment (as long as they have desired bioactivity) of formation.Blood white for acute myeloid sample For the treatment of sick (AML), the leukemia therapy of formula (I) compound and standard can be used in combination, especially and for AML The therapy for the treatment of is used in combination.Specifically, can by formula (I) compound and such as farnesyl tranfering enzyme inhibitor and/or its He for AML treatment drug for example daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, mitoxantrone, idarubicin, Carboplatin and PKC412 are administered in combination.

Formula (I) compound can also be advantageously utilised in the combination with other compounds or in the combination of other therapeutic agents, Especially other anti-malarial agents.Such anti-malarial agents include, but are not limited to chloroguanide (proguanil), Chlorproguanil (chlorproguanil), trimethoprim (trimethoprim), chloroquine (chloroquine), Mefloquine (mefloquine), Lumefantrine (lumefantrine), Atovaquone (atovaquone), pyrimethamine-sulfanilamide (SN) (pyrimethamine- Sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinindium (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfanilamide (SN) Class drug, qinghaosu, Arteflene (arteflene), Artemether, Artesunate, primaquine suck NO, L-arginine, dipropyl Alkene triamine NONO ester (NO donor), Rosiglitazone (PPARy agonist), active carbon, hematopoietin, levamisol, And Malaridine.

Formula (I) compound also may be advantageously used in the combination with other compounds or the combination of other therapeutic agents, example Such as treat the other therapeutic agents of leishmaniasis, trypanosomiasis, toxoplasmosis and cerebral cysticercosis.Such medicament includes, but are not limited to Nivaquin, atovaquone-proguanil, Artemether-lumenfantrine, quinine sulfate, Artesunate, quinine, fortimicin (doxycycline), clindamycin (clindamycin), meglumine antimony (meglumine antimoniate), gluconic acid Antimony sodium (sodium stibogluconate), Miltefosine (miltefosine), ketoconazole (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposome, paromomycin (paromomycine), Eflornithine (eflornithine), nifurtimox (nifurtimox), suramin (suramin), melarsoprol (melarsoprol), sprinkle Ni Songlong (prednisolone), benzimidazole, sulphadiazine, pyrimethamine, synergistic sulfonamide methylisoxazole, radonil, Ah Miramycin (azitromycin), Atovaquone, dexamethasone, praziquantel, albendazole (albendazole), beta-lactam, Fluoroquinolones medicine, macrolides medicine, aminoglycoside medicine, sulphadiazine and pyrimethamine.

The structure of the active constituent determined by code name, common name or trade name and its preparation can be from classic " The Merck Index (Merck index) " current edition (such as M.J.O ' Neil et al. is compiled, ' and The MerckIndex ', the 13rd Version, Merck Research Laboratories, 2001) or from database (such as Patents International (example Such as IMS World Publications)) in know.

Compound that is above-described, can using with formula (I) compound combination, can be pressed by those skilled in the art According to above-mentioned method preparation recorded in the literature and administration.Formula (I) compound can also be combined with therapeutic process, improve curative effect.Example Such as, hormone therapy or special radiotherapy are given.Formula (I) compound is used especially as radiosensitizer, it is especially useful in right The weak oncotherapy of those radiotherapeutic responses.

" combination " indicates the medicine box of the fixed Combination in single dose unit form or the part for combined administration, Middle formula (I) compound and combined partner can be applied in same time individual application or respectively at a certain time interval With, especially make combined partner show cooperation, for example act synergistically.Term " co-administration " as used in the present invention or " group Single individual (such as the patient) for being applied to selected COMBINATION OF THE INVENTION and a combination thereof being needed to apply is included in conjunction application " etc., and wraps Include wherein substance without going through identical administration method or the therapeutic scheme being administered simultaneously.Term " medicine group as used in the present invention Close product " it indicates to mix or combine obtained product for more than one active constituents, and both include the fixation of active constituent Combination also includes non-fixed combinations.Term " fixed Combination " indicate active constituent compound as shown in formula (I) and COMBINATION OF THE INVENTION with Single entities or the form of dosage are administered simultaneously in patient.Term " non-fixed combinations " indicates active constituent such as formula (I) shownization It closes object and COMBINATION OF THE INVENTION is used as corpus separatum to be successively applied to patient simultaneously, jointly or without specific time limitation ground, wherein should It is applied in patient's body and provides the treatment effective level of two kinds of compounds.The latter applies also for cocktail therapy, such as application 3 Kind or more active constituent.

The purposes of the compounds of this invention and pharmaceutical composition

The compounds of this invention is the inhibitor of kinase activity, especially the inhibitor of PI3- kinase activity.For PI3- kinases The compound of inhibitor can be used for treating that wherein potential pathology is (at least a part of) is attributed to improperly PI3- kinase activity Disorder, such as asthma and chronic obstructive pulmonary disease (COPD)." improperly PI3- kinase activity " refers to and in specific patient In desired normal PI3- kinase activity have any PI3- kinase activity of deviation.Improperly PI3- kinases can be taken, for example, living Property abnormal increase or the distortion of PI3- kinases or control not normal form.Improperly activity can be due to for these, such as causes not When or not controlled make the overexpression or mutation of protein kinase being activated.Therefore, on the other hand, the present invention relates to treatment institutes The method for stating disorder or disease.

Such disorder or disease include, but are not restricted to, respiratory disease, including asthma, chronic obstructive Tuberculosis and idiopathic pulmonary fibrosis (IPF)；Virus infection, including viral respiratory infection and viral respiratory disease are disliked Change, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Anaphylactia, including allergy Property rhinitis and atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple sclerosis；Diseases associated with inflammation, Including inflammatory bowel disease；Cardiovascular disease, including thrombosis and atherosclerosis；Malignant hematologic disease；Neurodegenerative disease； Pancreatitis；Multiple organ failure；Kidney trouble；Platelet aggregation；Cancer；Sperm motility；Graft rejection；Graft rejection； Injury of lungs；And pain, including pain relevant to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain, Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain after liver.? In one embodiment, such disorder includes respiratory disease, including asthma and chronic obstructive pulmonary disease (COPD)；Anaphylaxis Disease, including allergic rhinitis and atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple hard Change；Diseases associated with inflammation, including inflammatory bowel disease；Cardiovascular disease, including thrombosis and atherosclerosis；Malignant hematologic disease； Neurodegenerative disease；Pancreatitis；Multiple organ failure；Kidney trouble；Platelet aggregation；Cancer；Sperm motility；Transplanting row Reprimand；Graft rejection；Injury of lungs；And pain, including pain relevant to rheumatoid arthritis or osteoarthritis, backache, Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia after systemic inflammatorome pain, liver And central pain.

Treatment method of the invention include give patient in need with compound shown in safety and a effective amount of formula (I) or Its pharmaceutically acceptable salt.Each embodiment of the invention includes by giving patient in need with safety and a effective amount of Compound shown in formula (I) or its pharmaceutically acceptable salt, the method for any disorder or disease that the treatment present invention mentions.

Compound shown in formula (I) can be given to study subject by any suitable administration route or its is pharmaceutically acceptable Salt, including both Formulations for systemic administration and local administration.Formulations for systemic administration include oral administration, parenteral administration, cutaneous penetration and directly Enteral administration.Parenteral refer to except enteral or it is transdermal in addition to administration route, usually inject or be infused.Parenteral administration Including intravenous, intramuscular and subcutaneous injection or infusion.Local administration is including being applied to skin, and intraocular, ear, vagina Interior, sucking and intranasal administration.Sucking refers to the intrapulmonary for being administered to patient, sucks whether through oral cavity sucking or nasal cavity. In some embodiments, compound shown in formula (I) or its pharmaceutically acceptable salt can be administered orally.In other embodiments In, it can compound or its pharmaceutically acceptable salt shown in administration by inhalation formula (I).It in further embodiments, can be through intranasal Give compound shown in formula (I) or its pharmaceutically acceptable salt.

It can once give or give formula (I) compound or its pharmaceutically acceptable salt according to a dosage regimen, in institute State in dosage regimen, it is specified that period in give several dosage at various time intervals.For example, can give 1 time daily, 2 times, 3 times or 4 dosage.In some embodiments, 1 dosage is given once daily.In further embodiments, 2 dosage are given once daily. Dosage can be given until reaching required therapeutic effect or indefinitely maintaining desired therapeutic effect.Chemical combination shown in formula (I) The suitable dosage regimen of object or its pharmaceutically acceptable salt depends on the pharmacokinetic property of the compound, such as inhales It receipts, distribution and half-life period, can be determined by professional technician.In addition, suitable dosage regimen, when lasting including scheme Between, for formula (I) compound or its pharmaceutically acceptable salt, depending on the disorder treated or disease, receiving The disorder for the treatment of or the severity of disease, the age of patients receiving treatment and physical condition, patient under consideration medical history, same When therapy property, the effect and some factors in the knowledge and technical skill of professional technician of expected treatment.Profession Technical staff is also understood that according to individual patient to the reaction of dosage regimen or individual patient needs to change as time goes by When it may require that adjust suitable dosage regimen.

The compound of the present invention can with one or more other drugs simultaneously, before or after be administered.Change of the invention Closing object can be administered alone by identical or different administration route, or be given together in the same pharmaceutical composition with other drugs Medicine.

Pharmaceutical composition or combination of the invention can be about 1-1000mg active constituent for the individual of about 50-70kg, Or the unit dose of the active constituent of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg Amount.The treatment effective dose of compound, pharmaceutical composition or combinations thereof depends on species, weight, age and the individual disease of individual Disease, disorder or disease or severity to be treated.The doctor of this field common skill, clinician or animal doctor can be easily Determine the effective quantity for preventing, treating or inhibiting each active constituent of disorder or progression of disease.Dosage cited above is special Property used advantageous mammal, such as mouse, rat, dog, monkey or isolated organ, tissue and its sample external and It is confirmed in vivo studies.The compound of the present invention can use in vitro as a solution, such as aqueous solution, can also be in suspension Or the vein that the form of aqueous solution enterally, parenterally and preferably passes through uses in vivo.A effective amount of range of interior therapeutic depends on giving The approach of medicine, between about 0.01-500mg/kg, or about between 1-100mg/kg.

In addition, formula (I) compound represented can be administered with pro-drug.Term used in the present invention, chemistry " prodrug " of the compound of formula (I) is its functionality for finally discharging the compound of chemical formula (I) when delivering medicine to patient in vivo Derivative.When with the compound of prodrug administration chemistry formula (I), one of implementable following manner of those skilled in the art and with It is upper: (a) to change the internal onset time of compound；(b) the internal acting duration of compound is changed；(c) compound is changed It is internal conveying or distribution；(d) the internal solubility of compound is changed；And the side effect for (e) overcoming compound to be faced or its His difficult point.The typical functional derivatives of prodrug are used to prepare, comprising in vivo chemically or the mode of enzyme cracks The variant of compound.Comprising preparing these variants of phosphate, amide, ester, monothioester, carbonate and carbaminate to ability It is well-known for field technique personnel.

On the one hand, the present invention provides disease caused by unsuitable PI3K kinase activity or the treatment methods of disorder.Institute Stating treatment method includes by giving patient in need with safety and a effective amount of formula (I) compound or its is pharmaceutically acceptable Salt, the method for any disorder or disease that the treatment present invention mentions.

In some embodiments, the disease of unsuitable PI3- kinase activity mediation or disorder include: respiratory disease, such as Asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) etc.；Virus infection, including viral respiratory sense Dye and viral respiratory disease deteriorate, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and Li Shiman Disease；Allergic diseases, including allergic rhinitis and atopical dermatitis；Autoimmune disease, including rheumatoid close Section inflammation and multiple sclerosis；Inflammatory disease, including inflammatory bowel disease；Cardiovascular disease, including thrombosis and atherosclerosis；It dislikes Property blood disease；Neurodegenerative disease；Pancreatitis；Multiple organ failure；Nephrosis；Platelet aggregation；Cancer；Sperm motility；Transplanting Repel；Graft rejection；Injury of lungs；And pain, including pain relevant to rheumatoid arthritis or osteoarthritis, backache, Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia after systemic inflammatorome pain, liver And central pain.

The compounds of this invention can be used for treating the disease or sense of the immune system of one or more functions with B cell Dye, for example, antibody tormation, antibody present, cell factor generate or lymphoid organ formed abnormal or worthless illness, disease or The method of illness, the illness, disease or illness include that rheumatoid arthritis, pemphigus vulgaris, essential thrombocytopenia subtract Few property purpura, systemic loupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren syndrome, Autoimmune hemolytic are poor Blood, ANCA associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic auto-immune nettle rash, Allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), Goodpasture's syndrome, AMR (antibody-mediated transplanting Repel), the cancer of super acute, acute and chronic graft rejection and hematopoiesis source that mediates of B cell, including but not limited to multiple bone Myeloma；Acute myeloid leukaemia；Chronic myelogenous leukemia；Lymphocytic leukemia；Myeloid leukemia；Non-Hodgkin's lymph Tumor；Lymthoma；Polycythemia vera；Primary thrombocytosis；Myelofibrosis with metaplasia outside marrow；With watt Er Dengsitelun disease.

The present invention includes the one or more functions such as superoxides release for treating wherein neutrophil cell, is excited born of the same parents It spits or migration is abnormal or the method for worthless illness, disease or illness, the illness, disease or illness include rheumatoid Property arthritis, sepsis, lung or respiratory disorder such as asthma, inflammatory skin diseases such as psoriasis etc..

The present invention includes the one or more functions such as migration for treating wherein basophilic granulocyte and mast cell Or the threshing that mediates of allergen-IgE- is abnormal or the method for worthless illness, disease or illness, the illness, disease or disease Disease include anaphylactia (atopic dermatitis, contact dermatitis, allergic rhinitis) and other illnesss such as COPD, asthma or Pulmonary emphysema.

The present invention includes that one or more functions such as cell factor for the treatment of wherein T cell generates or cell-mediated thin Cellular toxicity is abnormal or the method for worthless illness, disease or illness, and the illness, disease or illness include that rheumatoid closes Save the acute or chronic repulsion of inflammation, multiple sclerosis, cell tissue or organ graft or the cancer in hematopoiesis source.

In addition, the present invention includes the method for treating neurodegenerative disease, cardiovascular disease and platelet aggregation.

In addition, the present invention includes treatment skin disease such as porphyria cutanea tarda, polymorphous light eruption (polymorphous light eruption), dermatomyositis, urticaria solaris, oral lichen planus, panniculitis, chorionitis, The method of urticarial vasculitis.

In addition, the present invention includes the method for treating chronic inflammatory disease such as sarcoidosis, granuloma annulare.

In other embodiments, illness or disorder (as PI3K is mediated) are selected from: polycythemia vera, primary Piastrenemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS (acute respiratory distress syndrome), Loew Le are comprehensive Simulator sickness, eosinophilic pneumonia, helminth (especially metazoa) infect (including increased tropical eosinophils), bronchus Pulmonary aspergilosis, eosinophilic granuloma, is influenced as caused by drug response nodular polyarteritis (including Qiu-this syndrome) The disorder related with acidophic cell of air flue, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, blister Rash sample dermatitis, chorionitis, leucoderma, allergic vasculitis, nettle rash, bullous pemphigoid, lupus erythematosus, pemphigus (pemphisus), posterior bullous epidermis release, (such as hemolytic anemia, aplastic are poor for autoimmune hematological disease Blood, pure red cell anaemia and essential thrombocytopenia are reduced), systemic loupus erythematosus, polychondritis, chorionitis, Wegener Granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, steven-Johnson syndrome, idiopathic sprue, itself Immunity inflammatory bowel disease (such as ulcerative colitis and Crohn disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, lung Steep inflammation, chronic anaphylaxis pneumonia, multiple sclerosis, primary biliary cirrhosis, (front and rear) uveitis, interstitial lung Fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular disease, atherosclerosis, hypertension, deep vein thrombosis shape At, it is apoplexy, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolysis disease, Acute arterial ischeamia, outer All thrombotic occlusions and coronary artery disease, reperfusion injury, retinopathy, such as diabetic retinopathy or hyperbaric oxygen draw The retinopathy risen, and illness, such as glaucoma characterized by increasing intraocular pressure or aqueous humor secretion.

It is pain by the disorder that unsuitable PI3K kinase activity mediates in some embodiments.

In another embodiment, the compounds of this invention can be used for treating illness or illness selected from the following: primary Cutaneous B cell lymphoma, immunity bubble disease (immunobullous disease), pemphigus vulgaris, fallen leaves property day Blister sore, Brazilian pemphigus (Fogo selvagem), tumour form sign pemphigus (paraneoplastic Pemphigus), bullous pemphigoid, mucosal pemphigus, acquired epidermolysis bullosa, the anti-place of chronic graft Main disease, dermatomyositis, systemic loupus erythematosus, vasculitis, polyangitis, low complement courage and uprightness urticarial vasculitis (hypocomplementemic urticarial vasculitis), anti-neutrophil cell cytoplasmic antibody associated vessels Inflammation cryoglobulinemia, Schnitzler syndrome, macroglobulinemia Waldenstron, angioedema, hickie, is System property lupus erythematosus, Idiopathic Thrombocytopenic Purpura, multiple sclerosis, cold coagulation disease, Autoimmune hemolytic are poor Blood, anti-neutrophil cell cytoplasmic antibody associated vasculitis, graft versus host disease(GVH disease), cryoglobulinemia and thrombotic blood are small Plate reduces disease.

In other embodiments, the present invention can be used for treating, prevent or alleviate autoimmunity disease and inflammatory disease, The especially teiology inflammatory condition that includes autoimmune component, for example, arthritis (such as rheumatoid arthritis, it is chronic into Fertility arthritis (arthritis chronic progrediente) and arthritis deformans) and rheumatic disease, including lead Relate to the inflammatory condition and rheumatic disease of bone lesion；(including ankylosing spondylitis, Josef Reiter are comprehensive for inflammatory pain, spondyloarthropathy Simulator sickness, adjuvant arthritis, psoriatic arthritis and enteropathic arthritis (enterophathics arthritis)), it is super quick Property (including air flue hypersensitivity and skin hypersensitivity) and allergy.The specific autoimmune disease packet of antibody of the present invention can be used Include autoimmune hematological illness (including such as hemolytic anemia, alpastic anemia, pure red cell anaemia and idiopathic Thrombopenia), it is Acquired hemophilia A, cold coagulation disease, cryoglobulinemia, thrombotic thrombocytopenic purpura, dry Dry syndrome, systemic loupus erythematosus, inflammatory muscular disorders, polychondritis, scleroderma, anti-neutrophil cell cytoplasmic antibody It is neuropathy that associated vasculitis, IgM are mediated, opsoclonia-myoclonic syndrome, wegener granulomatosis, dermatomyositis, slow Sexuality hepatitis, myasthenia gravis, psoriasis, Si-about syndrome, pemphigus vulgaris, pemphigus foliaceus, idiopathic mouth Inflammatory diarrhea, autoimmune inflammatory enteropathy (including such as ulcerative colitis, regional enteritis and irritable bowel syndrome), Endocrine ophthalmocace change, Graves disease, sarcoidosis, multiple sclerosis, neuromyelitis optica, primary biliary cirrhosis, children Year patients with type Ⅰ DM (type-1 diabetes mellitus), uveitis (anterior uveitis, intermediate uveitis and posterior uveitis and full grape Film is scorching), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with be not accompanied by nephrotic syndrome, for example including idiopathic nephrotic syndrome or minute nephropathy), tumour, skin and angle Film inflammatory disease, myositis, bone graft relaxation, metabolic disorder such as atherosclerosis, diabetes and dyslipidemia (dislipidemia)。

In some embodiments, the present invention provides the therapeutical uses of compound shown in formula (I), other embodiments, Treatment of the treatment for disease relevant to PI3K inhibiting effect.In other embodiments, the disease that can be treated Selected from above-mentioned list of diseases, including autoimmune disease, diseases associated with inflammation, anaphylactia, airway disorders (e.g., asthma and COPD), graft rejection；Antibody tormation, antibody present, cell factor generates or lymphoid organ formation is abnormal or worthless Conditions or diseases, including rheumatoid arthritis, pemphigus vulgaris, Idiopathic Thrombocytopenic Purpura, systemic erythema Lupus, multiple sclerosis, myasthenia gravis, Sjogren syndrome, autoimmune hemolytic anemia, ANCA associated vasculitis, (atopic dermatitis connects for cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic auto-immune nettle rash, allergy Touching property dermatitis, allergic rhinitis), Goodpasture's syndrome, AMR (antibody-mediated graft rejection), B cell mediate super urgency Property, acute and chronic graft rejection and hematopoiesis source cancer, including but not limited to Huppert's disease；Leukaemia；It is acute myelogenous white Blood disease；Chronic myelogenous leukemia；Lymphocytic leukemia；Myeloid leukemia；Non-Hodgkin lymphoma；Lymthoma；True property is red Cytosis；Primary thrombocytosis；Myelofibrosis with metaplasia outside marrow；And Waldenstrom.Its Described in conditions or diseases to be selected from rheumatoid arthritis (RA), pemphigus vulgaris (PV), idiopathic thrombocytopenic purple Purplish or white patches on the skin (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune hemolytic anemia (AIHA), Acquired hemophilia A Type (AHA), systemic loupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis (MG), Sjogren syndrome (SS), ANCA Associated vasculitis, cryoglobulinemia, chronic auto-immune nettle rash (CAU), allergy (atopic dermatitis, contact Dermatitis, allergic rhinitis), Goodpasture's syndrome, graft rejection and make haematogenous cancer；It equally can treat and immunological disease Relevant disease of science or infection, such as severe malaria, cerebral malaria, trypanosomiasis, leishmaniasis, toxoplasmosis and cerebral cysticercosis.

Therefore, in some more particular embodiments, the present invention relates to the compounds of any of above embodiment in PI3K The application of disease mediated therapeutic agent manufacture view；In other embodiments, the drug is that treatment inhibits to make with PI3K With the drug of relevant disease；In other embodiments, the disease that can be treated is selected from above-mentioned list of diseases, including itself Immunological diseases, diseases associated with inflammation, anaphylactia, airway disorders (e.g., asthma and COPD), graft rejection；Antibody tormation, antibody It presents, cell factor generates or lymphoid organ formation is abnormal or worthless conditions or diseases, including rheumatoid joint Inflammation, pemphigus vulgaris, Idiopathic Thrombocytopenic Purpura, systemic loupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren syndrome, autoimmune hemolytic anemia, ANCA associated vasculitis, cryoglobulinemia, Thrombotic Thrombocytopenic subtract Few property purpura, chronic auto-immune nettle rash, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), Gourde(G) pa Super acute, the acute and chronic graft rejection and hematopoiesis that this mound syndrome, AMR (antibody-mediated graft rejection), B cell mediate Source cancer, including but not limited to Huppert's disease；Leukaemia；Acute myeloid leukaemia；Chronic myelogenous leukemia；Lymphocyte Property leukaemia；Myeloid leukemia；Non-Hodgkin lymphoma；Lymthoma；Polycythemia vera；Idiopathic thrombocythemia Disease；Myelofibrosis with metaplasia outside marrow；And Waldenstrom.Wherein the conditions or diseases are selected from rheumatoid Arthritis (RA), pemphigus vulgaris (PV), Idiopathic Thrombocytopenic Purpura (ITP), thrombotic thrombocytopenic are purple Purplish or white patches on the skin (TTP), autoimmune hemolytic anemia (AIHA), Acquired hemophilia A type (AHA), systemic loupus erythematosus (SLE), It is multiple sclerosis (MS), myasthenia gravis (MG), Sjogren syndrome (SS), ANCA associated vasculitis, cryoglobulinemia, slow Property autoimmune urticaria (CAU), allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), Goodpasture are comprehensive Simulator sickness, graft rejection and make haematogenous cancer；It equally can treat disease relevant to immunopathology or infection, such as serious malaria Disease, cerebral malaria, trypanosomiasis, leishmaniasis, toxoplasmosis and cerebral cysticercosis.

General synthesis process

For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.

Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.

The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.

Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.The survey of nuclear magnetic resonance spectroscopy Strip part is: under room temperature, the nuclear magnetic resonance spectrometer of Brooker (Bruker) 400MHz or 600MHz, with CDC1₃、DMSO-d₆、CD₃OD Or acetone-d₆For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as reference standard.It is more when occurring When weight peak, following abbreviation will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, it is triple Peak), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), Dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).

The test condition of low resolution mass spectrometry (MS) data is: Agilent 6120Quadrupole HPLC-MS (pillar Model: Zorbax SB-C18,2.1x30mm, 3.5 μm, 6min, flow velocity 0.6mL/min, mobile phase: 5%-95% (contains The CH of 0.1% formic acid₃CN) in (H containing 0.1% formic acid₂O the ratio in)), it is detected in 210/254nm with UV, with electron spray electricity From mode (ESI).

The characteristic manner of compound purity are as follows: 1260 preparative high performance liquid chromatography of Agilent (Pre-HPLC) or 250 preparative high performance liquid chromatography of Calesep Pump (Pre-HPLC) (column model: NOVASEP, 50/80mm, DAC), 210nm/254nm is detected with UV.

The use of logogram word below is through the present invention:

ATP atriphos

AcOH,HAc,CH₃COOH acetic acid, acetic acid

AcOK potassium acetate

AIBN azodiisobutyronitrile

AlCl₃Aluminium chloride

BBr₃Boron tribromide

Bu₄NF, TBAF tetrabutyl ammonium fluoride

Burgess reagent (Burgess Reagent) N- (triethyl ammonium sulphonyl) methyl carbamate

BPO peroxidating (two) benzoyl

BSA bovine serum albumin(BSA)

BOC, Boc tert-butoxycarbonyl

N-BuOH n-butanol

N-BuLi n-BuLi

(n-Bu)₃SnCl tri-n-butyltin chloride

Cs₂CO₃Cesium carbonate

CCl₄Carbon tetrachloride

CH₂I₂Diiodomethane

CDCl₃Deuterated chloroform

CH₂Cl₂, DCM methylene chloride

CH₃CN, MeCN acetonitrile

CH₃SO₂Cl, MsCl methylsufonyl chloride

CH₃OH, MeOH methanol

CH₃I, MeI iodomethane

Cu copper

CuI cuprous iodide

DCC N, N '-dicyclohexylcarbodiimide

11 carbon -7- alkene of DBU 1,8- diazabicylo [5.4.0]

DIBAL diisobutyl aluminium hydride

DIAD diisopropyl azodiformate

DIEA, DIPEA, i-Pr₂Net N, N- diisopropylethylamine

DMF n,N-Dimethylformamide, dimethylformamide

DMAP 4-dimethylaminopyridine

DMAC DMAC N,N' dimethyl acetamide

DMSO dimethyl sulfoxide

DPPA diphenyl phosphate azide

DTT dithiothreitol

EDC, EDCI 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride

EDTA ethylenediamine tetra-acetic acid

EtOAc, EA ethyl acetate

Et₃N, TEA triethylamine

Et₂O ether

EtOH ethyl alcohol

FBS fetal calf serum

G grams

H hours

HBr hydrobromic acid

HCl hydrochloric acid

HOAc acetic acid

H₂O water

H₂O₂Hydrogen peroxide

H₃PO₄Phosphoric acid

H₂SO₄Sulfuric acid

HNO₃Nitric acid

HCOOK potassium formate

HMDS hmds

HPLC high pressure liquid chromatography or high performance liquid chromatography

I₂Iodine

I-PrMgBr isopropyl magnesium bromide

I-PrMgCl isopropylmagnesium chloride

Two silicon substrate base lithium of LiHMDS hexamethyl

LDA lithium diisopropyl amido

MBP myelin alkaline protein

MCPBA metachloroperbenzoic acid

MgSO₄Magnesium sulfate

ML, ml milliliters

Min minutes

N₂Nitrogen

NH₃Ammonia

NMP N-Methyl pyrrolidone

NaHCO₃Sodium bicarbonate

NaBH₄Sodium borohydride

NaBH₃CN sodium cyanoborohydride

NaOtBu sodium tert-butoxide

NaOMe, NaOCH₃Sodium methoxide

NaOH sodium hydroxide

NaClO₂Sodium chlorite

NaClO sodium hypochlorite

NaCl sodium chloride

NaH₂PO₄Sodium dihydrogen phosphate

NaH sodium hydride

NaI sodium iodide

Na₂SO₄Sodium sulphate

Na₂S₂O₃Sodium thiosulfate

NBS N-bromo-succinimide

NIS N- N-iodosuccinimide

NH₂OH azanol

NH₃Ammonia

NH₄Cl sal-ammoniac

Pd/C drapes over one's shoulders palladium/carbon

Pd(PPh₃)₄Tetrakis triphenylphosphine palladium

Pd(PPh₃)₂Cl₂Bis- (triphenylphosphine) palladium chlorides

Pd(dppf)Cl₂1,1 '-bis- (diphenylphosphine) ferrocene palladium chlorides

Pd(dppf)Cl₂·CH₂Cl₂[1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex

P(t-Bu)₃Three (tert-butyl) phosphines

PE petroleum ether (60-90 DEG C)

PBS phosphate buffered saline (PBS)

POCl₃Phosphorus oxychloride

PPA polyphosphoric acids

PhI(OAc)₂Iodobenzene diacetate

K₂CO₃Potassium carbonate

KOH potassium hydroxide

RT, rt, r.t. room temperature

Rt retention time

SOCl₂Thionyl chloride

SO₂Cl₂Sulfonic acid chloride

T-BuOK potassium tert-butoxide

THF tetrahydrofuran

TFA trifluoroacetic acid

TBAI tetrabutylammonium iodide

TBS trimethylolaminomethane buffered saline

TEAC bis- (tetraethyl ammonium) carbonate

TLC thin-layer chromatography

Tris trishydroxymethylaminomethane

Zn zinc

μ L microlitre

Synthetic schemes listed below gives the experimental procedure that compound is disclosed in the preparation present invention.Wherein, each X, W, R², R³And R⁴With definition as described in the present invention；R^hFor Cl, Br or I；" PG " is suitable alkynyl blocking group.

Synthetic schemes 1

Compound in the present invention can be prepared by method described in synthetic schemes 1.Firstly, compound(1)Iodide reaction occurs with NIS and generates compound(2).Then, the compound of iodo(2)Under suitable Pd catalyst action With alkynyl compounds(3)Undergo coupling reaction to produce compound(4).Finally, compound(4)With compound(5)In the effect of alkali Lower generation condensation reaction generates final kinase inhibitor(6)。

Synthetic schemes 2

Other compounds in the present invention can be prepared by method described in synthetic schemes 2.Firstly, iodine The compound in generation(2)With alkynyl compounds(7)Compound is undergone coupling reaction to produce under suitable Pd catalyst action(8)。 Then by compound in the presence ofs the aqueous solution of alkali or TBAF etc.(8)In alkynyl blocking group " PG " take off, generate intermediate(9)。

Compound(10)First in CuI, CH₂I₂It reacts in the presence of isoamyl nitrite, by compound(10)In ammonia Base is converted to iodine, generates compound(11).Compound(11)Again under suitable Pd catalyst action with intermediate(9)Occur even Connection reaction generates compound(4).Finally, compound(4)In the presence of base with compound(5)Condensation reaction occurs to generate finally Kinase inhibitor(6)。

Synthetic schemes 3

The preparation method of the compounds of this invention is also illustrated in synthetic schemes 3.Firstly, having the alkynyl compounds of protecting group(8)Under alkaline condition with compound(5)Condensation reaction occurs and generates compound(12).Then, compound(12)In the water of alkali The blocking group " PG " on alkynyl is taken off in the presence of solution or TBAF etc., generates final kinase inhibitor(13)。

Synthetic schemes 4

Compound in the present invention can also be prepared by method described in above-mentioned synthetic schemes 4.Firstly, chemical combination Object(2)Under alkaline condition with compound(5)Condensation reaction occurs and generates compound(14).Then, compound(14)Suitable Pd catalyst action under with alkynyl compounds(3)Undergo coupling reaction to produce final kinase inhibitor(6)。

Synthetic schemes 5

Compound in the present invention can also be prepared by method described in above-mentioned synthetic schemes 5.Firstly, chemical combination Object(15)Borate under suitable Pd catalyst action with pyrazole derivatives(16)Coupling generates compound(17).Compound(17)The blocking group taken off on amino in acid condition generates intermediate(18).Then, intermediate(18)In alkaline condition Lower and compound(2)Condensation reaction occurs and generates compound(19).Finally, compound(19)Under suitable Pd catalyst action With alkynyl compounds(3)Undergo coupling reaction to produce final kinase inhibitor(20)。

Specific embodiment

The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..

Embodiment 1 (S) -2- (1- ((6- amino -5- ((3- aminophenyl) acetenyl) pyrimidine-4-yl) amino) propyl) - Chloro- 3- cyclopropyl quinazoline -4 (3H) -one of 5-

The chloro- 5- iodine pyrimidine -4- amine of step 1) 6-

Compound 6- chlorine pyrimidine -4- amine (1.29g, 10mmol) is dissolved in DMF (8mL), it is then disposable thereto It is added N- N-iodosuccinimide (2.25g, 10mmol), obtains yellow mixture, reaction mixture is stirred to react at 100 DEG C It after 8 hours, is cooled to room temperature, then is concentrated under reduced pressure, residue is dissolved in EtOAc (300mL), gained mixture is first with saturation The washing of the mixed liquor (1/2 (v/v), 100mL x3) of sodium thiosulfate solution and saturated sodium bicarbonate aqueous solution, then successively use Water (150mL x3) and saline solution (100mL) washing.Organic phase is dry with anhydrous sodium sulfate, then is concentrated under reduced pressure, gained residue It is purified through silica gel column chromatography (PE/EtOAc (v/v)=5/1), obtaining title compound is white solid (1.20g, 47.0%).

MS(ESI,pos.ion)m/z:255.8[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.12(s,1H)。

Step 2) 5- ((3- aminophenyl) acetenyl) -6- chlorine pyrimidine -4- amine

Under nitrogen protection, to the chloro- 5- iodine pyrimidine -4- amine (200mg, 0.783mmol) of compound 6-, Pd (PPh₃)₂Cl₂ Sequentially added in the mixture of (27mg, 0.04mmol) and CuI (7mg, 0.04mmol) 3- acetylenylaniline (138mg, DMF (0.5mL) solution 1.17mmol), DMF (0.5mL) solution and DMF (1mL) of triethylamine (158mg, 1.57mmol), institute It obtains mixture to be stirred to react at 35 DEG C 6 hours, EtOAc (15mL) diluted mixture is then added, mixture successively uses water again (10mL x3) and saline solution (10mL) washing, organic phase be concentrated under reduced pressure, residue through silica gel column chromatography (PE/EtOAc (v/v)= 2/1) it purifies, obtaining title compound is faint yellow solid (178mg, 92.9%).

MS(ESI,pos.ion)m/z:245.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.33 (s, 1H), 7.19 (t, J=7.8Hz, 1H), 6.99-6.94 (m, 1H), 6.91-6.84 (m, 1H), 6.74 (ddd, J=8.1,2.4,0.9Hz, 1H), 5.65 (s, 2H), 3.77 (s, 2H).

Step 3) (S) -2- (1- ((6- amino -5- ((3- aminophenyl) acetenyl) pyrimidine-4-yl) amino) propyl) -5- Chloro- 3- cyclopropyl quinazoline -4 (3H) -one

By compound 5- ((3- aminophenyl) acetenyl) -6- chlorine pyrimidine -4- amine (50mg, 0.204mmol) and (S) -2- Chloro- 3- cyclopropyl quinazoline -4 (3H) -one (62mg, 0.225mmol) of (1- aminopropyl) -5- is suspended in n-BuOH (3mL), Then DIPEA (53mg, 0.408mmol) is added thereto to be cooled to room temperature after gained mixture is heated to reflux 24 hours, then It is concentrated under reduced pressure, residue is diluted in EtOAc (20mL), mixture is successively washed with water (20mL x2) and saline solution (20mL) Wash, organic phase is dry with anhydrous sodium sulfate, then is concentrated under reduced pressure, gained residue through silica gel column chromatography (DCM/MeOH (v/v)= 50/1) it purifies, obtaining title compound is yellow solid (42mg, 42.3%).

MS(ESI,pos,ion):486.3[M+H]⁺；HPLC:96.6%；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.14(s,1H),7.55-7.49(m,1H),7.49-7.40(m,2H), 7.25-7.17 (m, 1H), 7.01 (d, J=7.7Hz, 1H), 6.94-6.87 (m, 1H), 6.74 (dd, J=8.0,1.5Hz, 1H), 6.55 (d, J=8.6Hz, 1H), 6.23-6.10 (m, 1H), 5.16 (s, 2H), 3.77 (s, 2H), 3.11-3.00 (m, 1H), 2.15-2.03 (m, 1H), 1.97-1.85 (m, 1H), 1.48-1.43 (m, 2H), 1.18-1.12 (m, 1H), 1.03 (t, J= 7.4Hz,3H),0.89-0.84(m,1H)。

Embodiment 2 (S) -2- (1- ((6- amino -5- (phenylacetylene base) pyrimidine-4-yl) amino) propyl) chloro- 3- cyclopropyl of -5- Base quinazoline -4 (3H) -one

Step 1) 6- chloro- 5- (phenylacetylene base) pyrimidine -4- amine

Under nitrogen protection, to the chloro- 5- iodine pyrimidine -4- amine (200mg, 0.783mmol) of compound 6-, Pd (PPh₃)₂Cl₂ Phenylacetylene (141mg, 1.38mmol) is sequentially added in the mixture of (27mg, 0.04mmol) and CuI (7mg, 0.04mmol) DMF (0.5mL) solution, DMF (0.5mL) solution and DMF (1mL) of triethylamine (158mg, 1.57mmol).Reaction solution is at 35 DEG C Under be stirred to react 4 hours after, EtOAc (15mL) dilution is added, gained mixture successively uses water (10mL x3) and saline solution (10mL) washing, organic phase are concentrated under reduced pressure, and gained residue is obtained through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purifying Title compound is brown solid (130mg, 72.3%).

MS(ESI,pos.ion.)m/z:230.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.35(s,1H),7.62-7.53(m,2H),7.47-7.35(m,3H), 5.66(s,2H)。

Step 2) (S) -2- (1- ((6- amino -5- (phenylacetylene base) pyrimidine-4-yl) amino) propyl) chloro- 3- cyclopropyl of -5- Base quinazoline -4 (3H) -one

By compound 6- chloro- 5- (phenylacetylene base) pyrimidine -4- amine (50mg, 0.218mmol) and (S) -2- (1- aminopropan Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (63mg, 0.229mmol) of -5- is suspended in n-BuOH (3mL), then to it Middle addition DIPEA (56mg, 0.435mmol).It after gained mixture is heated to reflux 24 hours, is cooled to room temperature, then is concentrated under reduced pressure, Then EtOAc (20mL) is added and dilutes residue, gained mixture is successively washed with water (20mL x2) and saline solution (20mL), had Machine is mutually dry with anhydrous sodium sulfate, then is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=100/1) It is yellow solid (40mg, 39.0%) that purifying, which obtains title compound,.

MS(ESI,pos,ion):471.1[M+H]⁺；HPLC:97.9%；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.16(s,1H),7.64-7.57(m,2H),7.55-7.48(m,1H), 7.48-7.39 (m, 5H), 6.56 (d, J=8.7Hz, 1H), 6.19 (td, J=7.6,5.2Hz, 1H), 5.15 (s, 2H), 3.11- 3.02(m,1H),2.15-2.03(m,1H),1.97-1.86(m,1H),1.50-1.42(m,2H),1.19-1.11(m,1H), 1.04 (t, J=7.4Hz, 3H), 0.94-0.87 (m, 1H).

Embodiment 3 (S) -2- (1- ((6- amino -5- ((1- methyl-1 H- pyrazole-3-yl) acetenyl) pyrimidine-4-yl) ammonia Base) propyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

The iodo- 1- methyl-1 H- pyrazoles of step 1) 3-

Under nitrogen protection, compound 1- methyl-1 H- pyrazoles -3- amine (200mg, 2.06mmol) is suspended in THF In (5mL), CuI (431mg, 2.27mmol) and CH are then added thereto₂I₂(0.5mL, 6.18mmol), next adds Amyl nitrite (8.30mL, 61.78mmol).After mixture is heated to reflux 5 hours, it is cooled to room temperature, is then added EtOAc (15mL) dilution, the Na of gained mixture saturation₂S₂O₃Aqueous solution (15mL) washing, then filtered through silicagel pad, filtrate It is washed with saturated salt solution (10mL), organic phase is dry with anhydrous sodium sulfate, is then concentrated under reduced pressure.Gained residue is through silicagel column It is yellow liquid (233mg, 54.4%) that chromatography (PE/EtOAc (v/v)=10/1) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:209.0[M+H]⁺。

The chloro- 5- of step 2) 6- ((trimethylsilyl) acetenyl) pyrimidine -4- amine

Under nitrogen protection, to the chloro- 5- iodine pyrimidine -4- amine (500mg, 0.196mmol) of compound 6-, Pd (PPh₃)₂Cl₂ In the mixture of (69mg, 0.10mmol) and CuI (19mg, 0.10mmol) be added trimethylsilyl acetylene (1.38mL, DMF (1.5mL) solution of DMF (1.5mL) solution and triethylamine (0.54mL, 3.91mmol) 9.79mmol), by mixture plus Heat is to 47 DEG C and is stirred to react 2 hours, is then added EtOAc (30mL) dilution, gained mixture successively use water (20mL x2) and Saline solution (20mL) washing, liquid separation, obtained organic phase is dry with anhydrous sodium sulfate, then is concentrated under reduced pressure, and gained residue is through silicon It is brown solid (442mg, 100%) that plastic column chromatography (PE/EtOAc (v/v)=10/1) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:226.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.31(s,1H),5.62(s,2H),0.31(s,9H)。

The chloro- 5- acetylene yl pyrimidines -4- amine of step 3) 6-

The chloro- 5- of compound 6- ((trimethylsilyl) acetenyl) pyrimidine -4- amine (200mg, 0.886mmol) is dissolved in In THF (4mL), TBAF (tetrahydrofuran solution of 1M, 0.9mL) then is added thereto, gained mixture is stirred at room temperature After reaction 2 hours, it is concentrated under reduced pressure, residue is diluted in EtOAc (15mL), gained mixture saturation Na₂CO₃Aqueous solution Isolated organic phase is concentrated under reduced pressure for (15mL x2) washing, liquid separation, and obtaining title compound is brown solid, the solid Without being further purified, it is directly used in and reacts in next step.

MS(ESI,pos.ion)m/z:154.1[M+H]⁺。

The chloro- 5- of step 4) 6- ((1- methyl-1 H- pyrazole-3-yl) acetenyl) pyrimidine -4- amine

Under nitrogen protection, by whole brown solids obtained in the previous step, Pd (PPh₃)₂Cl₂(31mg, 0.044mmol) and CuI (8mg, 0.044mmol) is suspended in DMF (2mL), then thereto be added the iodo- 1- methyl-1 H- pyrazoles of 3- (170mg, 0.817mmol) with DMF (1.5mL) solution of triethylamine (179mg, 1.77mmol), heats the mixture to 80 DEG C and stir anti- It answers 16 hours, EtOAc (20mL) dilution is then added, obtained mixture successively uses water (20mL x2) and saline solution (20mL) Wash, liquid separation, by obtained organic phase be concentrated under reduced pressure, by gained residue be suspended in mixed solvent PE/EtOAc (5/1 (v/v), In 12mL), after reaction being stirred at room temperature 4 hours, filtering.The solid being collected into is rinsed with PE (10mL), and is dried under reduced pressure, and is obtained It is the yellow orange solid (gross production rate of 139mg, step 4 and step 5 liang step: 72.8%) to title compound.

MS(ESI,pos.ion.)m/z:234.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.22 (s, 1H), 7.79 (d, J=2.2Hz, 1H), 6.64 (d, J= 2.2Hz,1H),3.89(s,3H)。

Step 5) (S) -2- (1- ((6- amino -5- ((1- methyl-1 H- pyrazole-3-yl) acetenyl) pyrimidine-4-yl) ammonia Base) propyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound 6- ((1- methyl-1 H- pyrazole-3-yl) acetenyl) pyrimidine -4- amine (50mg, 0.214mmol) Chloro- 3- cyclopropyl quinazoline -4 (3H) -one (89mg, 0.321mmol) of (S) -2- (1- aminopropyl) -5- is suspended in n-BuOH In (3mL), DIPEA (55mg, 0.428mmol) is then added thereto and is cooled to after gained mixture is heated to reflux 23 hours Room temperature, then be concentrated under reduced pressure.Residue is diluted in EtOAc (20mL), gained mixture successively uses water (20mL x2) and salt Water (20mL) washing, organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=50/1 it) purifies, obtaining title compound is yellow solid (49mg, 48.2%).

MS(ESI,pos,ion):475.2[M+H]⁺；HPLC:98.1%；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.13(s,1H),7.58-7.46(m,2H),7.48-7.37(m,2H), 6.58-6.45(m,2H),6.20-6.09(m,1H),5.26(s,2H),4.00(s,3H),3.12-3.01(m,1H),2.06- 2.00 (m, 1H), 1.98-1.83 (m, 1H), 1.50-1.40 (m, 2H), 1.22-1.11 (m, 1H), 1.03 (t, J=7.3Hz, 3H),0.95-0.86(m,1H)。

Embodiment 4 (S) -2- (1- ((6- amino -5- acetenyl pyrimidine-4-yl) amino) ethyl) chloro- 3- cyclopropyl quinoline of -5- Oxazoline -4 (3H) -one

Step 1) (S) -2- (1- ((6- amino -5- ((trimethylsilyl) acetenyl) pyrimidine-4-yl) amino) ethyl) - Chloro- 3- cyclopropyl quinazoline -4 (3H) -one of 5-

By the chloro- 5- of compound 6- ((trimethylsilyl) acetenyl) pyrimidine -4- amine (103mg, 0.443mmol) and (S) - Chloro- 3- cyclopropyl quinazoline -4 (3H) -one (144mg, 0.548mmol) of 2- (1- amino-ethyl) -5- is suspended in n-BuOH (8mL) In, DIPEA (118mg, 0.913mmol) then is added into reaction solution, reaction solution is heated to flow back and stir in seal pipe Reaction 30 hours is mixed, is then cooled to room temperature, is concentrated under reduced pressure, ethyl acetate (25mL) is added and dilutes residue, obtained mixing Object is successively washed with water (25mL) and saline solution (20mL), liquid separation, and obtained organic phase is dry with anhydrous sodium sulfate, is then depressurized dense Contracting, residue through silica gel column chromatography (PE/EtOAc (v/v)=3/2) purifying obtain title compound be yellow solid (100mg, 48.4%).

MS(ESI,pos,ion):453.2[M+H]⁺。

Step 2) (S) -2- (1- ((6- amino -5- acetenyl pyrimidine-4-yl) amino) ethyl) chloro- 3- cyclopropyl quinoline of -5- Oxazoline -4 (3H) -one

By compound (S) -2- (1- ((6- amino -5- ((trimethylsilyl) acetenyl) pyrimidine-4-yl) amino) second Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (80mg, 0.177mmol) of -5- is dissolved in THF (3mL), then in room temperature condition Under, TBAF (THF solution of 1M, 0.18mL, 0.18mmol) is added into reaction solution, after reaction being stirred at room temperature 1 hour, depressurizes dense Contracting is added EtOAc (25mL) and dilutes residue, and obtained mixture successively uses saturated aqueous sodium carbonate (20mL x2) and food Salt water (20mL) is washed, liquid separation, and obtained organic phase is dry with anhydrous sodium sulfate, is concentrated under reduced pressure, residue preparative thin layer color It is faint yellow solid (62mg, 92.2%) that spectrum (PE/EtOAc (v/v)=1/4) purifying, which obtains title compound,.

MS(ESI,Pos.ion.)m/z:381.2[M+H]⁺；HPLC:96.2%；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.14 (s, 1H), 7.62-7.49 (m, 2H), 7.45 (dd, J=7.3, 1.7Hz, 1H), 6.49 (d, J=8.0Hz, 1H), 6.17 (dq, J=13.3,6.6Hz, 1H), 5.17 (s, 2H), 3.87 (s, 1H), 3.13-2.99 (m, 1H), 1.61 (d, J=6.6Hz, 3H), 1.48-1.40 (m, 2H), 1.18-1.09 (m, 1H), 0.99- 0.91(m,1H)。

Embodiment 5 (S) -2- (1- ((6- amino -5- (propyl- 1- alkynes -1- base) pyrimidine-4-yl) amino) ethyl) chloro- 3- of -5- Cyclopropyl quinazoline -4 (3H) -one

The chloro- 5- of step 1) 6- (propyl- 1- alkynes -1- base) pyrimidine -4- amine

Under nitrogen protection, to the chloro- 5- iodine pyrimidine -4- amine (205mg, 0.803mmol) of compound 6-, Pd (PPh₃)₂Cl₂ Sequentially added in the mixture of (28mg, 0.04mmol) and CuI (8mg, 0.04mmol) propine (3% hexane solution, 5.36g, DMF (2mL) solution and triethylamine (162mg, 1.61mmol) 4.01mmol), reaction solution after 35 DEG C are stirred to react 24 hours, DMF layers of organic phase are separated, and ethyl acetate (15mL) dilution is added, obtained mixture successively uses water (20mL) and food Salt water (10mL) is washed, liquid separation, by obtained organic phase be concentrated under reduced pressure, residue first through silica gel column chromatography (PE/EtOAc (v/v)= 4/1) it purifies, then obtaining title compound with preparative thin-layer chromatography (PE/EtOAc (v/v)=1/1) purifying is pale solid (20mg, 14.9%).

MS(ESI,Pos.ion.)m/z:168.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.28(s,1H),5.55(s,2H),2.21(s,3H)。

Step 2) (S) -2- (1- ((6- amino -5- (propyl- 1- alkynes -1- base) pyrimidine-4-yl) amino) ethyl) chloro- 3- of -5- Cyclopropyl quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (propyl- 1- alkynes -1- base) pyrimidine -4- amine (19mg, 0.113mmol) and (S) -2- (1- amino Ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (36mg, 0.136mmol) of -5- is suspended in n-BuOH (2mL), then to DIPEA (29mg, 0.227mmol) is added in reaction solution, is heated to flowing back, and be stirred to react 46 hours, then cool to room temperature, It is concentrated under reduced pressure, residue successively uses preparative thin-layer chromatography (PE/EtOAc (v/v)=1/5) and preparative thin-layer chromatography (DCM/ MeOH (v/v)=30/1) purifying obtain title compound be yellow solid (14mg, 31.3%).

MS(ESI,pos,ion):395.2[M+H]⁺；HPLC:99.1%；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.09 (s, 1H), 7.60-7.53 (m, 1H), 7.50 (dd, J=8.1, 1.3Hz, 1H), 7.44 (dd, J=7.6,1.3Hz, 1H), 6.40 (d, J=8.2Hz, 1H), 6.14 (dq, J=13.5,6.7Hz, 1H), 5.10 (s, 2H), 3.11-3.01 (m, 1H), 2.27 (s, 3H), 1.60 (d, J=6.7Hz, 3H), 1.46-1.41 (m, 2H),1.18-1.11(m,1H),0.96-0.90(m,1H)。

Embodiment 6 (S) -2- (1- ((6- amino -5- (3- hydroxy-3-methyl butyl- 1- alkynes -1- base) pyrimidine-4-yl) amino) Ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

Step 1) (S) -2- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) chloro- 3- cyclopropyl quinazoline-of -5- 4 (3H) -one

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- amino-ethyl) -5- (50mg, 0.189mmol), the chloro- 5- iodine pyrimidine -4- amine (48mg, 0.189mmol) of 6-, DIPEA (49mg, 0.379mmol) and n-BuOH The mixture of (1mL) is heated to flowing back and being stirred to react 16 hours, then cools to room temperature, and is concentrated under reduced pressure, residue is through silica gel It is faint yellow solid (49mg, 53%) that column chromatography (DCM/MeOH (v/v)=100/1) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:483.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.98 (s, 1H), 7.55-7.53 (m, 2H), 7.43-7.41 (dd, J= 3.6,5.6Hz, 1H), 6.41-6.39 (d, J=7.8Hz, 1H), 6.12-6.05 (m, 1H), 5.04 (s, 2H), 3.05-3.03 (m, 1H), 1.59-1.57 (d, J=6.2Hz, 3H), 1.43-1.41 (m, 2H), 1.14-1.10 (m, 1H), 0.95-0.86 (m, 1H)。

Step 2) (S) -2- (1- ((6- amino -5- (3- hydroxy-3-methyl butyl- 1- alkynes -1- base) pyrimidine-4-yl) amino) Ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

To compound (S) -2- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) the chloro- 3- cyclopropyl quinoline azoles of -5- Quinoline -4 (3H) -one (49mg, 0.103mmol), CuI (2mg, 0.01mmol), Pd (PPh₃)₂Cl₂(8mg, 0.01mmol) and DMF 2- methyl butyl- 3- alkynes -2- alcohol (13mg, 0.155mmol) is added in the mixture of (2mL), next adds triethylamine Reaction solution is heated to 90 DEG C by (0.07mL, 0.518mmol), and is stirred to react 16 hours, is then cooled to room temperature, and is depressurized dense Contracting, obtained residue are washed with saturated salt solution (4mL), dry with anhydrous sodium sulfate, are concentrated under reduced pressure, residue is through silica gel column layer It is faint yellow solid (21mg, 46%) that analysis (DCM/MeOH (v/v)=100/5) purifying, which obtains title compound,.

MS(ESI,Pos.ion)m/z:439.0[M+H]⁺；HPLC:96%；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.10 (s, 1H), 7.54-7.50 (m, 2H), 7.43-7.41 (d, J= 7.0Hz, 1H), 6.53-6.51 (d, J=8.1Hz, 1H), 6.18-6.11 (dddd, J=6.4,6.4,6.4,6.4Hz, 1H), 5.13 (s, 2H), 3.05-2.99 (m, 1H), 2.01 (br s, 1H), 1.58-1.56 (d, J=6.6Hz, 3H), 1.44-1.42 (m,2H),1.25(s,6H),1.06-1.03(m,1H),0.87-0.86(m,1H)。

Embodiment 7 (S) -3- (1- ((6- amino -5- (propyl- 1- alkynes -1- base) pyrimidine-4-yl) amino) ethyl) -2- cyclopropyl Base -8- (1- methyl-1 H- pyrazoles -4- base) isoquinolin -1 (2H) -one

Step 1) (S)-(1- (2- cyclopropyl -8- (1- methyl-1 H- pyrazoles -4- base) -1- oxo -1,2- dihydro-isoquinoline - 3- yl) ethyl) t-butyl carbamate

By compound (S)-(1- (the chloro- 2- cyclopropyl -1- oxo -1,2- dihydro-isoquinoline -3- base of 8-) ethyl) amino first Tert-butyl acrylate (1.69g, 4.66mmol), 1- methyl -4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) - 1H- pyrazoles (1.46g, 7.02mmol), sodium carbonate (990mg, 9.34mmol), water (7mL) and n,N-dimethylacetamide (7mL) Mixture be heated to 120 DEG C and be stirred to react 3.5 hours, then cool to room temperature, water (60mL) and ethyl acetate be added (60mL) dilution, liquid separation, obtained organic phase are washed with water (60mL) and saturated salt solution (60mL), are concentrated under reduced pressure, gained residual It is yellow solid (1.4g, 73.7%) that object, which obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=1/6) purifying,.

MS(ESI,pos.ion)m/z:408.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.60 (s, 1H), 7.57 (s, 1H), 7.51-7.47 (dd, J=7.6, 7.6Hz, 1H), 7.34-7.32 (d, J=7.6Hz, 1H), 7.28-7.26 (d, J=8.0Hz, 1H), 6.44 (s, 1H), 5.54- 5.51 (m, 1H), 4.79-4.77 (d, J=6.4Hz, 1H), 3.96 (s, 3H), 2.91-2.85 (m, 1H), 1.48-1.46 (d, J =6.8Hz, 3H), 1.44 (s, 9H), 1.28-1.25 (m, 2H), 1.04 (m, 1H), 0.78-0.73 (m, 1H).

Step 2) (S) -3- (1- amino-ethyl) -2- cyclopropyl -8- (1- methyl-1 H- pyrazoles -4- base) isoquinolin -1 (2H) -one

By compound (S)-(1- (2- cyclopropyl -8- (1- methyl-1 H- pyrazoles -4- base) -1- oxo -1,2- dihydro isoquinoline Quinoline -3- base) ethyl) t-butyl carbamate (1.40g, 3.43mmol) is dissolved in methylene chloride (4mL), then to reaction solution The middle ethyl acetate solution (3M, 20mL) that hydrogen chloride is added, is stirred at room temperature reaction 2 days, is then concentrated under reduced pressure, residue is dissolved In water (30mL), gained mixture is extracted with ethyl acetate (20mLx2), and NaHCO is added in water phase₃Powder is adjusted to pH= 8.5, and extracted with methylene chloride (30mL x2), combined organic phase is washed with saturated salt solution (30mL), dry with anhydrous sodium sulfate Dry, being concentrated under reduced pressure to give title compound is white solid (800mg, 75.7%).

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.61 (s, 1H), 7.58 (s, 1H), 7.52-7.48 (d, J=7.6, 7.6Hz, 1H), 7.37-7.35 (d, J=8.0Hz, 1H), 7.27-7.26 (m, 1H), 6.60 (s, 1H), 4.79 (q, J= 6.4Hz, 1H), 3.96 (s, 3H), 2.93-2.88 (m, 1H), 1.46-1.44 (d, J=6.5Hz, 3H), 1.30-1.22 (m, 2H),0.80-0.77(m,2H)。

Step 3) (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) -2- cyclopropyl -8- (1- methyl - 1H- pyrazoles -4- base) isoquinolin -1 (2H) -one

By compound (S) -3- (1- amino-ethyl) -2- cyclopropyl -8- (1- methyl-1 H- pyrazoles -4- base) isoquinolin -1 (2H) -one (101mg, 0.3275mmol), the chloro- 5- iodine pyrimidine -4- amine (88.2mg, 0.345mmol) of 6- and DIPEA (165.7mg, 1.282mmol) is suspended in n-butanol (1mL), and gained mixture is stirred to react 6 under 150 DEG C and microwave condition Hour, it then cools to room temperature, is concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=30/1) Obtaining title compound is faint yellow solid (76mg, 44%).

MS(ESI,pos.ion)m/z:527.7[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.95(s,1H),7.61(s,1H),7.58(s,1H),7.49(dd,J =7.6,7.6Hz, 1H), 7.33-7.31 (d, J=7.2Hz, 1H), 7.27-7.25 (d, J=7.2Hz, 1H), 6.41 (s, 1H), 6.01-5.94 (m, 1H), 5.21-5.19 (d, J=7.2Hz, 1H), 5.09 (br s, 2H), 3.96 (s, 3H), 2.922.87 (m, 1H), 1.61-1.59 (d, J=6.8Hz, 3H), 1.28-1.25 (m, 2H), 0.82-0.79 (m, 2H).

Step 4) (S) -3- (1- ((6- amino -5- (propyl- 1- alkynes -1- base) pyrimidine-4-yl) amino) ethyl) -2- cyclopropyl Base -8- (1- methyl-1 H- pyrazoles -4- base) isoquinolin -1 (2H) -one

To compound (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) -2- cyclopropyl -8- (1- first Base -1H- pyrazoles -4- base) isoquinolin -1 (2H) -one (69mg, 0.13mmol), triethylamine (0.1mL, 0.7mmol) and DMF It is passed through nitrogen in the mixture of (2mL) 10 minutes, drains air, iodate Asia is then sequentially added under -10 DEG C and nitrogen atmosphere Copper (11mg, 0.058mmol), Pd (Ph₃)₂Cl₂(25mg, 0.036mmol) and propine (2mL).Gained mixture is stirred at room temperature Reaction 30 minutes, is then heated to 90 DEG C and continues to be stirred to react 16 hours, be cooled to room temperature, and it is dilute that methylene chloride (20mL) is added It releases, gained mixture is washed with water (25mL x2), is then concentrated under reduced pressure, and gained residue is through silica gel column chromatography (DCM/MeOH (v/ V) it is faint yellow solid (30mg 46.96%) that=10/1) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:440.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.06(s,1H),7.62(s,1H),7.58(s,1H),7.51-7.47 (dd, J=7.6,7.6Hz, 1H), 7.34-7.33 (d, J=6.8Hz, 1H), 7.27-7.26 (d, J=8.0Hz, 1H), 6.46 (s, 1H), 6.04-5.97 (m, 1H), 5.28-5.26 (d, J=7.6Hz, 1H), 5.11 (br s, 2H), 3.97 (s, 3H), 2.92-2.87 (m, 1H), 2.19 (s, 3H), 1.59-1.58 (d, J=5.2Hz, 3H), 1.25-1.22 (m, 2H), 0.82-0.76 (m,2H)。

Embodiment 8 (S) -2- (1- ((6- amino -5- (pyrimidine -5- ethyl-acetylene base) pyrimidine-4-yl) amino) ethyl) -3- ring Propyl -5- (1- methyl-1 H- pyrazoles -4- base) quinazoline -4 (3H) -one

Step 1) (S)-(1- (3- cyclopropyl -5- (1- methyl-1 H- pyrazoles -4- base) -4- oxo -3,4- dihydroquinazoline - 2- yl) ethyl) t-butyl carbamate

To compound (S)-(1- (the chloro- 3- naphthenic base -4- oxo -3,4- dihydroquinazoline -2- base of 5-) ethyl) amino first Tert-butyl acrylate (500mg, 1.37mmol), 1- methyl -4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) - Pd (dppf) Cl is added in the mixture of 1H- pyrazoles (429mg, 2.06mmol) and DMAC N,N' dimethyl acetamide (10mL)₂· CH₂Cl₂The aqueous solution (4.0mL) of (113mg, 0.14mmol) and sodium carbonate (437mg, 4.12mmol) then leads into reactant Enter nitrogen 2 minutes, drain air, then reactant is heated to 120 DEG C and is stirred to react 4 hours, then cool to room temperature, is added Water (10mL) quenching reaction, with suction filtered through kieselguhr, filtrate is extracted with ethyl acetate (20mL x3), and combined organic phase is with anhydrous Sodium sulphate is dry, is concentrated under reduced pressure, and gained residue obtains targeted through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying Conjunction object is light yellow oil (507mg, 90.0%).

MS(ESI,pos.ion)m/z:410.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 7.85 (s, 1H), 7.69-7.65 (t, J=7.8Hz, 1H), 7.54 (s, 1H), 7.46-7.44 (dd, J=8.0,0.9Hz, 1H), 7.34-7.29 (t, J=8.8Hz, 2H), 3.88 (s, 3H), 2.98-2.91(m,1H),1.99-1.96(m,1H),1.49-1.30(m,12H),0.99-0.91(m,2H),0.86-0.84(m, 2H)。

Step 2) (S) -2- (1- amino-ethyl) -3- cyclopropyl -5- (1- methyl-1 H- pyrazoles -4- base) quinazoline -4 (3H) -one

By compound (S)-(1- (3- cyclopropyl -5- (1- methyl-1 H- pyrazoles -4- base) -4- oxo -3,4- dihydro quinoline azoles Quinoline -2- base) ethyl) t-butyl carbamate (507mg, 1.24mmol) is dissolved in ethyl acetate (6mL), then to reaction solution The middle ethyl acetate solution (3.0M, 4.0mL) that hydrogen chloride is added, is stirred at room temperature reaction 5 hours, is then concentrated under reduced pressure, will remain Object is suspended in methylene chloride (20mL), and saturated sodium bicarbonate aqueous solution is added and is adjusted to neutrality obtained suspended matter, water phase It is extracted with methylene chloride (10mL x2), combined organic phase is dry with anhydrous sodium sulfate, and being concentrated under reduced pressure to give target compound is Pale brown oil object (322mg, 84.0%).

MS(ESI,pos.ion)m/z:310.2[M+H]⁺。

Step 3) (S) -2- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) -3- cyclopropyl -5- (1- methyl - 1H- pyrazoles -4- base) quinazoline -4 (3H) -one

By compound (S) -2- (1- amino-ethyl) -3- cyclopropyl -5- (1- methyl-1 H- pyrazoles -4- base) quinazoline -4 (3H) -one (120.0mg, 0.39mmol) and the chloro- 5- iodine pyrimidine -4- amine (99.2mg, 0.39mmol) of 6- are dissolved in n-BuOH In (1.5mL), DIPEA (0.2mL, 1.00mmol) then is added into reaction solution, mixture is in 160 DEG C, under microwave condition It is stirred to react 5 hours, is then concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=50/1) It is yellow solid (95mg, 46.3%) to title compound.

MS(ESI,pos.ion)m/z:528.7[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆) δ (ppm): 7.87 (d, J=11.1Hz, 1H), 7.76-7.66 (m, 2H), 7.55 (s, 1H), 7.50-7.45 (m, 1H), 7.33 (d, J=7.5Hz, 1H), 6.60 (d, J=7.5Hz, 1H), 6.49 (s, 2H), 5.96-5.87 (m, 1H), 3.88 (s, 3H), 3.04 (m, 1H), 1.55 (d, J=6.6Hz, 3H), 1.04 (m, 2H), 0.85 (m, 2H)。

Step 4) (S) -2- (1- ((6- amino -5- (pyrimidine -5- ethyl-acetylene base) pyrimidine-4-yl) amino) ethyl) -3- ring Propyl -5- (1- methyl-1 H- pyrazoles -4- base) quinazoline -4 (3H) -one

By compound (S) -2- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) -3- cyclopropyl -5- (1- first Base -1H- pyrazoles -4- base) quinazoline -4 (3H) -one (40.0mg, 0.08mmol) and 5- acetylene yl pyrimidines (12.0mg, It 0.12mmol) is dissolved in DMF (1.5mL), Pd (PPh is then added into reaction solution₃)₂Cl₂(11.0mg, 0.02mmol), iodine Change cuprous (2.0mg, 0.01mmol) and triethylamine (0.05mL, 0.4mmol), gained mixture is stirred in 90 DEG C under nitrogen protection Reaction 17 hours is mixed, is then cooled to room temperature, is concentrated under reduced pressure, gained residue chromatographs (DCM/MeOH (v/v) through Flash silica column =20/1) it is white-yellowish solid (9.0mg, 23.5%) that purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:505.4[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.23(s,1H),8.97(s,2H),8.22(s,1H),7.67(s, 1H), 7.66-7.65 (t, J=7.7Hz, 1H), 7.63 (s, 1H), 7.43-7.42 (dd, J=8.1,1.1Hz, 1H), 7.35- 7.33 (dd, J=7.5,1.2Hz, 1H), 6.86-6.85 (d, J=7.8Hz, 1H), 6.22-6.18 (dq, J=13.4,6.7Hz, 1H), 5.37 (s, 2H), 4.00 (s, 3H), 3.03-2.99 (m, 1H), 1.65-1.64 (d, J=6.6Hz, 3H), 1.44-1.42 (m,2H),1.06-1.01(m,1H),0.87-0.86(m,1H)。

Embodiment 9 (S) -3- (1- ((6- amino -5- (3- hydroxy-3-methyl butyl- 1- alkynes -1- base) pyrimidine-4-yl) amino) Ethyl) chloro- 2- phenyl isoquinolin quinoline -1 (2H) -one of -8-

Step 1) (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) chloro- 2- phenyl isoquinolin quinoline -1 of -8- (2H) -one

By chloro- 2- phenyl isoquinolin quinoline -1 (2H) -one of compound (S) -3- (1- amino-ethyl) -8- (202mg, 0.676mmol), the chloro- 5- iodine pyrimidine -4- amine (257mg, 1.0mmol) of 6- and triethylamine (340mg, 3.36mmol) are in n-BuOH Mixture in (2.0ml) is heated to flow back and continues to be stirred to react 47 hours, then cools to room temperature, and is concentrated under reduced pressure, gained Residue through silica gel column chromatography (DCM/MeOH (v/v)=100/1) purifying obtain title compound be faint yellow solid (145mg, 41%).

MS(ESI,pos.ion)m/z:517.6[M+H]⁺。

Step 2) (S) -3- (1- ((6- amino -5- (3- hydroxy-3-methyl butyl- 1- alkynes -1- base) pyrimidine-4-yl) amino) Ethyl) chloro- 2- phenyl isoquinolin quinoline -1 (2H) -one of -8-

By compound (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) the chloro- 2- phenyl isoquinolin quinoline-of -8- 1 (2H) -one (100mg, 0.193mmol), cuprous iodide (4.5mg, 0.024mmol) and Pd (PPh₃)₂Cl₂(28.7mg, 0.040mmol) be suspended in anhydrous DMF (3mL), be then first added into reaction solution 2- methyl butyl- 3- alkynes -2- alcohol (23.4mg, 0.278mmol), triethylamine (0.14ml, 0.99mmol) is next added, acquired solution is heated to 90 DEG C and continues to stir Reaction 46 hours, then cools to room temperature, and water (15mL) quenching reaction is added, and gained mixture is with methylene chloride (30mL x3) Extraction, combined organic phase are washed with saturated salt solution (20mL), dry with anhydrous sodium sulfate, are concentrated under reduced pressure, gained residue warp It is faint yellow solid (20mg, 22%) that silica gel column chromatography (DCM/MeOH (v/v)=100/5) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:474.8[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ (ppm): 7.89 (s, 1H), 7.43 (ddd, J=20.0,13.4,7.5Hz, 8H), 6.56 (s, 1H), 4.86-4.73 (m, 1H), 4.08 (d, J=6.4Hz, 1H), 1.63 (s, 9H).

Embodiment 10 (S) -3- (1- ((6- amino -5- (propyl- 1- alkynes -1- base) pyrimidine-4-yl) amino) ethyl) -8- is chloro- 2- cyclopropyl isoquinolin -1 (2H) -one

Step 1) (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) chloro- 2- cyclopropyl isoquinolin-of -8- 1 (2H) -one

By chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of compound (S) -3- (1- amino-ethyl) -8- (1.012g, 3.852mmol), the chloro- 5- iodine pyrimidine -4- amine (1.04g, 4.07mmol) of 6- and triethylamine (993mg, 7.606mmol) are in n- Mixture in BuOH (10mL) is heated to 125 DEG C and continues to be stirred to react 48 hours, then cools to room temperature, and is concentrated under reduced pressure, The crude product that gained residue is obtained through silica gel column chromatography (DCM/MeOH (v/v)=100/1) purifying is again through silica gel column chromatography It is faint yellow solid (430mg.23.1%) that (EtOAc/PE (v/v)=1/2) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:482.7[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 7.80 (s, 1H), 7.52 (t, J=7.7Hz, 1H), 7.43 (dd, J =14.1,7.3Hz, 2H), 6.56 (s, 1H), 6.45 (s, 2H), 6.17 (d, J=7.2Hz, 1H), 5.80 (p, J=6.7Hz, 1H), 2.98 (m, 1H), 1.56 (d, J=6.8Hz, 3H), 1.26-1.19 (m, 2H), 1.16 (m, 2H).

Step 2) (S) -3- (1- ((6- amino -5- (propyl- 1- alkynes -1- base) pyrimidine-4-yl) amino) ethyl) chloro- 2- of -8- Cyclopropyl isoquinolin -1 (2H) -one

By compound (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) the chloro- 2- cyclopropyl isoquinoline of -8- Quinoline -1 (2H) -one (45mg, 0.0934mmol) is suspended in n,N-Dimethylformamide (1.5mL), then at room temperature, Cuprous iodide (9mg, 0.0473mmol) and Pd (PPh are added into reactant₃)₂Cl₂(10.2mg, 0.0144mmol), by gained Mixture substitutes gas (nitrogen) 10 minutes, and then at -10 DEG C, triethylamine (0.07g, 0.7mmol) is sequentially added into reaction solution With propyl alcohol (1.8mL, 0.96mmol, the n-heptane solution of mass fraction 3%), mixture is stirred overnight at 90 DEG C, is subsequently cooled to Ethyl acetate (60mL) dilution is added in room temperature, and liquid separation, organic phase is washed with water (20mL x2), decompression dry with anhydrous sodium sulfate Concentration, it is yellow solid that gained residue, which obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=30/1) purifying, (15mg, 41%).

MS(ESI,pos.ion)m/z:394.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.05(s,1H),7.42-7.37(m,2H),7.32-7.28(m,1H), 6.41 (s, 1H), 6.02-5.97 (m, 1H), 5.25 (d, J=7.4Hz, 1H), 5.04 (s, 2H), 2.95 (ddd, J=11.1, 7.0,4.3Hz,2H),2.20(s,3H),1.30-1.28(m,4H),0.90-0.86(m,4H)。

Embodiment 11 (S) -3- (1- ((6- amino -5- acetenyl pyrimidine-4-yl) amino) ethyl) -2- cyclopropyl -8- fluorine Isoquinolin -1 (2H) -one

Step 1) (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) -2- cyclopropyl -8- fluorine isoquinolin - 1 (2H) -one

By -1 (2H) -one of compound (S) -3- (1- amino-ethyl) -2- cyclopropyl -8- fluorine isoquinolin (425mg, 1.726mmol), the chloro- 5- iodine pyrimidine -4- amine (463.8mg, 1.816mmol) of 6- and DIPEA (445.5mg, 3.447mmol) exist Mixture in n-butanol (2.5mL) is heated to 130 DEG C and continues to be stirred to react 30 hours, then cools to room temperature, and depressurizes dense Contracting, gained residue obtain crude product through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purifying, and gained crude product is again through silicon It is faint yellow solid (250mg, 31%) that plastic column chromatography (PE/EtOAc (v/v)=1/3) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:466.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ (ppm): 7.94 (s, 1H), 7.48 (td, J=8.0,4.8Hz, 1H), 7.26 (s, 1H), 7.16-7.15 (d, J=7.8Hz, 1H), 7.03-7.00 (dd, J=11.4,7.8Hz, 1H), 6.39 (s, 1H), 5.98- 5.94 (dq, J=7.2,7.2Hz, 1H), 5.19-5.18 (d, J=7.2Hz, 1H), 5.10 (br s, 2H), 2.98-2.90 (m, 1H), 1.59-1.58 (d, J=6.6Hz, 3H), 1.35-1.33 (m, 2H), 1.27-1.24 (m, 1H), 0.92-0.86 (m, 1H).

Step 2) (S) -3- (1- ((6- amino -5- ((trimethyl silicon substrate) acetenyl) pyrimidine-4-yl) amino) ethyl) -2- - 1 (2H) -one of cyclopropyl -8- fluorine isoquinolin

By compound (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) -2- cyclopropyl -8- fluorine isoquinoline Quinoline -1 (2H) -one (50.0mg, 0.107mmol) and triethylamine (55.2mg, 0.546mmol) are dissolved in N,N-dimethylformamide In (2mL), then at 60 DEG C, Pd (PPh is added into reaction solution₃)₂Cl₂(7.4mg, 0.011mmol) and cuprous iodide (3.8mg, 0.020mmol) then adds trimethyl acetenyl silicon (29.2mg, 0.297mmol).Mixture is stirred at 60 DEG C Reaction 2 hours, then cools to room temperature, and ethyl acetate (20mL) dilute reaction solution is added, and gained mixture successively uses water (50mL X2 it) washes and is washed with saturated salt solution (50mL), filter, filtrate decompression is concentrated, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/2 it is faint yellow solid (29mg, 62%) that) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:436.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ (ppm): 8.06 (s, 1H), 7.47-7.46 (m, 1H), 7.16-7.15 (d, J= 8.4Hz, 1H), 7.03-7.00 (dd, J=11.4,8.4Hz, 1H), 6.42 (s, 1H), 6.015.96 (dt, J=6.6,6.6Hz, 1H), 5.33-5.32 (d, J=6.6Hz, 1H), 5.12 (br s, 2H), 2.97-2.94 (m, 1H), 1.57-1.56 (d, J= 6.6Hz, 3H), 1.36 (dd, J=15.1,8.4Hz, 3H), 1.37-1.24 (m, 3H), 0.92-0.86 (m, 1H), 0.28 (s, 9H)。

Step 3) (S) -3- (1- ((6- amino -5- acetenyl pyrimidine-4-yl) amino) ethyl) -2- cyclopropyl -8- fluorine is different Quinoline -1 (2H) -one

By compound (S) -3- (1- ((6- amino -5- ((trimethyl methyl silicon substrate) acetenyl) pyrimidine-4-yl) amino) second Base) -2- cyclopropyl -8- fluorine isoquinolin -1 (2H) -one (25mg, 0.057mmol) be dissolved in THF (2mL), then in room temperature condition Under, tetrabutyl ammonium fluoride (THF solution of 1M, 0.1mL) is added into reaction solution, 30 points of reaction is stirred at room temperature in acquired solution Then saturation NaHCO is added in clock₃Aqueous solution (10mL) and ethyl acetate (20mL) quenching reaction, liquid separation, organic phase saturation food Salt water (15mL) is washed, and is concentrated under reduced pressure, and gained residue obtains title through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying Compound is white-yellowish solid (14mg, 67%).

MS(ESI,pos.ion)m/z:364.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ (ppm): 8.09 (s, 1H), 7.49-7.46 (td, J=7.8,7.8,4.8Hz, 1H), 7.17-7.16 (d, J=7.8Hz, 1H), 7.04-7.00 (dd, J=10.8,7.8Hz, 1H), 6.43 (d, J=1.8Hz, 1H), 6.03-5.99 (dq, J=6.6,6.6Hz, 1H), 5.34-5.33 (d, J=7.2Hz, 1H), 5.15 (br s, 2H), 3.82 (s, 1H), 2.96-2.92 (dddd, J=6.6,6.6,4.2,4.2Hz, 1H), 1.58-1.57 (d, J=6.6Hz, 3H), 1.361.26(m,3H),0.91-0.86(m,1H)。

Embodiment 12 (S) -3- (1- ((6- amino -5- ((3- methoxyphenyl) acetenyl) pyrimidine-4-yl) amino) second Base) -1 (2H) -one of -2- cyclopropyl -8- fluorine isoquinolin

By compound (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) -2- cyclopropyl -8- fluorine isoquinoline Quinoline -1 (2H) -one (70mg, 0.1504mmol), 1- acetenyl -3- methoxybenzene (33.9mg, 0.257mmol) and triethylamine (78.9mg, 0.780mmol) is dissolved in n,N-Dimethylformamide (2mL), then at room temperature, is added into reaction solution Enter Pd (PPh₃)₂Cl₂(11.6mg, 0.0165mmol) and cuprous iodide (5.4mg, 0.028mmol), mixture this temperature after It is continuous to be stirred to react 2 hours, it is then heated to 60 DEG C and continues to be stirred to react 2 hours, be cooled to room temperature, ethyl acetate is added (20mL) dilution, gained mixture are successively washed with water (50mL x2) and saturated salt solution (50mL), are concentrated under reduced pressure, gained residual Object obtains crude product through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purifying, and gained crude product is through preparative TLC (PE/ EtOAc (v/v)=1/1) purifying obtain title compound be faint yellow solid (20mg, 28%).

MS(ESI,pos.ion)m/z:470.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.10 (s, 1H), 7.50-7.44 (m, 1H), 7.30-7.26 (dd, J= 8.0,8.0Hz, 1H), 7.17-7.15 (d, J=7.6Hz, 1H), 7.12-7.10 (d, J=7.6Hz, 1H), 7.03-6.99 (m, 2H), 6.94-6.92 (d, J=8.4Hz, 1H), 6.45 (s, 1H), 6.05-6.02 (m, 1H), 5.35-6.29 (d, J=7.2Hz, 1H), 5.18 (br s, 2H), 3.82 (s, 3H), 2.96-2.95 (m, 1H), 1.60-1.59 (d, J=7.2Hz, 3H), 1.36- 1.30(m,3H),0.89-0.87(m,H)。

Embodiment 13 (S) -3- (1- ((6- amino -5- (pyrimidine -5- ethyl-acetylene base) pyrimidine-4-yl) amino) ethyl) -8- Chloro- 2- phenyl isoquinolin quinoline -1 (2H) -one

To compound (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) the chloro- 2- phenyl isoquinolin quinoline-of -8- 1 (2H) -one (50.8mg, 0.0981mmol), cuprous iodide (2.2mg, 0.012mmol) and Pd (PPh₃)₂Cl₂(14.3mg, 0.020mmol) mixture in anhydrous DMF (2mL) sequentially adds 5- acetylene yl pyrimidines (31.6mg, 0.304mmol) and three Ethamine (0.05mL, 0.40mmol).Acquired solution is heated to 75 DEG C and continues to be stirred to react 5 hours, is cooled to room temperature, is added Water (15mL) quenching reaction, gained mixture are extracted with methylene chloride (30mL x3), combined organic phase saturated salt solution (20mL) is washed, dry with anhydrous sodium sulfate, is concentrated under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=100/ 5) it is faint yellow solid (30mg, 41.3%) that purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:494.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆) δ (ppm): 9.12 (d, J=6.4Hz, 2H), 7.89 (s, 1H), 7.60 (d, J= 3.9Hz, 2H), 7.55-7.32 (m, 7H), 6.88 (d, J=6.7Hz, 2H), 6.75 (s, 1H), 4.75-4.61 (m, 1H), 1.33 (d,3H)。

Embodiment 14 (S) -3- (1- ((6- amino -5- (3- hydroxy-3-methyl butyl- 1- alkynes -1- base) pyrimidine-4-yl) ammonia Base) ethyl) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-

By compound (S) -3- (1- ((6- amino -5- iodine pyrimidine -4- base) amino) ethyl) the chloro- 2- cyclopropyl isoquinoline of -8- Quinoline -1 (2H) -one (50.9mg, 0.106mmol) is dissolved in anhydrous DMF (4mL), then under nitrogen protection into reaction solution It sequentially adds triethylamine (43.1mg, 0.426mmol), cuprous iodide (4.5mg, 0.024mmol) and Pd (PPh₃)₂Cl₂ Gained mixture is heated to 60 DEG C by (7.2mg, 0.010mmol), then 2- methyl butyl- 3- alkynes -2- is added dropwise into reaction solution Alcohol (15mg, 0.178mmol), gained mixture are stirred to react 48 hours at 60 DEG C, then cool to room temperature, and are added water (20mL) Dilution, gained mixture are extracted with ethyl acetate (20mL x4), are washed with saturated salt solution (20mL x2), are concentrated under reduced pressure, gained Residue through silica gel column chromatography (EtOAc/PE (v/v)=1/1) purifying obtain title compound be white solid (3.6mg, 7.8%).

MS(ESI,pos.ion)m/z:438.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.08 (s, 1H), 7.41 (d, J=4.0Hz, 2H), 6.40 (s, 1H), 6.09-5.90 (m, 1H), 5.28 (d, J=7.0Hz, 1H), 5.14 (s, 2H), 4.14 (d, J=7.2Hz, 1H), 2.98 (s, 1H), 2.06 (s, 1H), 1.69 (s, 6H), 1.59 (d, J=6.5Hz, 3H), 1.35 (s, 2H), 0.90 (s, 2H).

Biologic test

The LC/MS/MS system of analysis includes the serial vacuum degassing furnace of Agilent 1200, and binary syringe pump, orifice plate is certainly Dynamic sampler, column insulating box, charged spray ionize the Agilent G6430 three-level level four bars mass spectrograph in the source (ESI).Quantitative analysis It is carried out under MRM mode, the parameter of MRM conversion is as in Table A:

Table A

More reaction detection scannings	490.2→383.1
		Fragmentation voltage	230V

Capillary voltage	55V
		Dryer temperature	350℃
Atomizer	40psi
		Drier flow velocity	10L/min

Analysis uses Agilent XDB-C18,2.1x30mm, 3.5 μM column, injects 5 μ L samples.Analysis condition: mobile phase For 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient such as table Shown in B:

Table B

Time	The gradient of Mobile phase B
		0.5min	5%
1.0min	95%
		2.2min	95%
2.3min	5%
		5.0min	Stop

In addition, the also 6330 series LC/MS/MS spectrometer of Agilent for analysis, is infused equipped with G1312A binary Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrometer uses ESI radioactive source.Use titer Suitable cationic model treatment is carried out to each analyte and MRM conversion carries out optimal analysis.It uses during analysis Capcell MP-C18 column, specification are as follows: 100x4.6mm I.D., 5 μM (Phenomenex, Torrance, California, USA).Mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70: 30, v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L samples.

Embodiment A: stability of the compound in people and rat liver microsomes

People or rat liver microsomes are placed in duplicate hole in polypropylen tubes to be incubated for.It is typical be incubated for mixed liquor include people or Rat liver microsomes (0.5mg protein/mL), target compound (5 μM) and total volume are NADPH (1.0mM) phosphoric acid of 200 μ L Potassium buffer (PBS, 100mM, pH value 7.4), compound is dissolved in DMSO, and is diluted using PBS, keeps it final DMSO solution concentration be 0.05%.And be incubated in the water-bath communicated at 37 DEG C with air, preincubate 3 minutes are backward Albumen is added in mixed liquor and starts to react.It is ice-cold that same volume is added in point (0,5,10,15,30 and 60min) in different times Acetonitrile terminates reaction.Sample is saved at -80 DEG C until carrying out LC/MS/MS analysis.

It determines the linear concentration range of each target compound, then, target is measured by the method for LC/MS/MS Concentration of the compound in the mixtures incubated of people or rat liver microsomes.

It is parallel to be incubated for test and use the microsome of denaturation as negative control, hatch at 37 DEG C, reaction is when different Between point (0,15 and 60min) terminate.

Dextromethorphan (70 μ Μ) be used as positive control, hatch at 37 DEG C, reaction in different times point (0,5,10, 15,30 and 60min) it terminates.It all include positive and negative control sample in each measuring method, to guarantee that microsome hatches body The integrality of system.In addition, stability data of the compound of the present invention in people or rat liver microsomes can also be by following examination It tests to obtain.People or rat liver microsomes are placed in duplicate hole in polypropylen tubes to be incubated for.Typical mixtures incubated include people or Rat liver microsomes (ultimate density: 0.5mg albumen/mL), compound (ultimate density: 1.5 μM) and total volume are the K- of 30 μ L Buffer solution (EDTA containing 1.0mM, 100mM, pH 7.4).Compound is dissolved in DMSO, and is diluted with K- buffer solution, Make the ultimate density 0.2% of DMSO.After ten minutes, it is anti-that 15 μ L NADPH (ultimate density: 2mM) progress enzymatic is added in preincubate It answers, entire test carries out in 37 DEG C of incubation tube.135 μ L acetonitriles are added in point (0,15,30 and 60 minute) in different times (containing IS) terminates reaction.With 4000rpm centrifugation 10 minutes, deproteinized is removed, supernatant liquor is collected, is analyzed with LC-MS/MS.

In above-mentioned test, ketanserin (1 μM) is selected as positive control, hatches at 37 DEG C, and reaction is in different times It terminates within point (0,15,30 and 60 minute).It all include positive control sample in each measuring method, to guarantee that microsome hatches body The integrality of system.

Data analysis

For each reaction, concentration (as a percentage) of the compound in people or rat liver microsomes are incubated for is pressed The plotted as percentage of opposite zero time point infers internal liver clearance rate CL with this_int(ref.:Naritomi Y, Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.)。

Stability data of 1 embodiment of the present invention of table in people and rat liver microsomes

Embodiment B: the pharmacokinetics after mouse, rat, dog and monkey intravenous injection and oral the compounds of this invention is commented Valence

The present invention comments the compounds of this invention in mouse, rat, dog or the intracorporal pharmacokinetic of monkey Estimate.The compounds of this invention is with aqueous solution or the aqueous solution of 2%HPMC+1% Tween-80, the saline solution of 5%DMSO+5%, and 4% MC or capsule form are administered.Intravenous injection is administered, animal gives the dosage of 1 or 2mg/kg.For oral dose (p.o.), rat and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25,0.5,1.0,2.0 at time point, Blood (0.3mL) is taken within 3.0,4.0,6.0,8.0,12 and 24 hours, and is centrifuged 10 minutes at 3,000 or 4,000rpm.Collect blood Solution is starched, and is saved at -20 DEG C or -70 DEG C until carrying out above-mentioned LC/MS/MS analysis.

2 embodiment of the present invention of table is in the intracorporal pharmacokinetic data of rat

Table 2 is as the result is shown: the compounds of this invention is preferable in rat body absorption, and half-life period is more reasonable.

Embodiment C: Kinase activity assays

The compounds of this invention can be evaluated as the activity of PI3K and mTOR kinase inhibitor by following tests 's.

The general description of kinase assay

Kinase assay passes through detection incorporation γ-³³The myelin basic protein (MBP) of P-ATP is come what is completed.Prepare 20 μ g/ MBP (Sigma#M-1891) trishydroxymethylaminomethane buffer salt solution (TBS of mL；50mM Tris pH 8.0,138mM NaCl, 2.7mM KCl), it is coated with white 384 orifice plate (Greiner) of high associativity, every 60 μ L of hole.It 4 DEG C, is incubated for 24 hours.Later With 100 μ L TBS board-washing 3 times.Kinase reaction is in kinase buffer liquid (the 5mM Hepes pH 7.6,15mM that total volume is 34 μ L NaCl, 0.01% bovine serum albumin(BSA) (Sigma#I-5506), 10mM MgCl₂, 1mM DTT, 0.02%TritonX-100) in It carries out.Compound is dissolved in DMSO, is added in each hole, the ultimate density of DMSO is 1%.Twice of each data determination, often The measurement of a compound is at least tested twice.For example, the ultimate density of enzyme is 10nM or 20nM.Addition does not have markd ATP (10 μM) and γ-³³(the every hole 2 × 10 ATP of P label⁶Cpm, 3000Ci/mmole) start to react.Reaction is shaken at room temperature It swings and carries out 1 hour.384 orifice plates are cleaned with the PBS of 7x, and the scintillation solution of every 50 μ L of hole is then added.It is counted with Wallac Trilux Number device testing result.To those of ordinary skill in the art, this is only one of numerous detection methods, other methods Also may be used.

The IC of the above-mentioned available inhibition of test method₅₀And/or inhibition constant K_i。IC₅₀It is defined as under test conditions, suppression Make compound concentration when 50% enzymatic activity.The curve comprising 10 concentration points is made using the extension rate of 1/2log, is estimated IC₅₀Value (for example, making a typical curve by following compound concentration: 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM and 0 μM).

The ordinary test scheme of PI3- kinases

PI3K (p110 α/p85 α) (h) [cold test]

PI3K (p110 α/p85 α) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask determining) buffer solution in be incubated for.After ATP solution is added, start to react.At room temperature be incubated for 30 minutes after, thereto plus Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acid to terminate reaction.Finally, detection buffering is added Liquid, the anti-GST monoclonal antibody including europium label, the GRP1PH structural domain and streptavidin-allophycocyanin of GST label.Orifice plate when Between read under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000x (Em665nm/ Em620nm it) determines.

PI3K (p110 β/p85 α) (h) [cold test]

PI3K (p110 β/p85 α) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask determining) buffer solution in be incubated for.After ATP solution is added, start to react.At room temperature be incubated for 30 minutes after, thereto plus Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acid to terminate reaction.Finally, detection buffering is added Liquid, the anti-GST monoclonal antibody including europium label, the GRP1PH structural domain and streptavidin-allophycocyanin of GST label.Orifice plate when Between read under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000x (Em665nm/ Em620nm it) determines.

PI3K (p110 δ/p85 α) (h) [cold test]

PI3K (p110 δ/p85 α) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask determining) buffer solution in be incubated for.After ATP solution is added, start to react.At room temperature be incubated for 30 minutes after, thereto plus Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acid to terminate reaction.Finally, detection buffering is added Liquid, the anti-GST monoclonal antibody including europium label, the GRP1PH structural domain and streptavidin-allophycocyanin of GST label.Orifice plate when Between read under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000x (Em665nm/ Em620nm it) determines.

PI3K (p120 γ) (h) [cold test]

PI3K (p120 γ) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is true according to demand It is incubated in buffer solution calmly).After ATP solution is added, start to react.After being incubated for 30 minutes at room temperature, it is added contains thereto There is the terminate liquid of EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acid to terminate reaction.Finally, detection buffer is added, Anti- GST monoclonal antibody including europium label, the GRP1PH structural domain and streptavidin-allophycocyanin of GST label.Orifice plate is in the time point It distinguishes and is read under fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000x (Em665nm/ Em620nm it) determines.

mTOR(h)

The HEPES that mTOR (h) is 7.0 in 50mM pH value, 1mM EDTA, 0.01% polysorbas20,2mg/mL substrate, 3mM chlorine Change manganese and [γ-³³P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing. Start to react after MnATP mixture is added.After being incubated for 40 minutes at room temperature, 3% phosphoric acid solution is added thereto and terminates reaction. 10 μ L reaction solutions are distributed on P30 filter in mottled, and are cleaned in 5 minutes 3 times with 75mM phosphoric acid, and dry and It is put into methanol solution and saves at once before scinticounting.

Kinase assay in the present invention be completed by Millipore company, Britain (Millipore UK Ltd, Dundee Technology Park,Dundee DD21SW,UK)。

The kinase inhibition data of 3 embodiment of the present invention of table

Table 3 is as the result is shown: the compounds of this invention has good inhibitory activity to the δ hypotype in PI3K kinase families.

The kinase inhibiting activity of the compounds of this invention can also pass through KINOMEscan^TMTest, it is mainly based upon quantitative Measure the ligand of sample and fixed, active site guiding and the test of kinases competitive binding ability.This is tested complete At need combine following three elements: DNA- label kinases, fixation ligand and sample to be tested.Sample to be tested and fixed ligands The ability of competitive binding kinases can be determined by the amount of the PCR in measurement DNA marker.

For most of tests, kinases-label T7 phage strain is the large intestine bar that origin is derived from BL21 bacterial strain Bacterium host is prepared.I.e. first by Escherichia coli cultivate to logarithmic growth phase, then infected with T7 bacteriophage, and by its It by lysate centrifugation, filters until cracking in 32 DEG C of hatchings under continuous concussion, removes cell fragment.It is remaining in HEK-293 And then the kinases generated into the cell is marked with DNA, the detection for qPCR.It is coated with the magnetic bead and biology of Streptavidin After the smaller ligand of elementization reacts 30 minutes at room temperature, the affine resin for being used for kinase assay is generated.The magnetic bead being coordinated It is blocked by excessive biotin, with blocking buffer (SEABLOCK^TM(Pierce), 1%BSA, 0.05% Tween-20,1mM DTT) washing removes free ligand, to reduce non-specific binding.Association reaction is all by kinases, the compatibility being coordinated Magnetic bead and sample to be tested in 1x combination buffer (20%SEABLOCK^TM, 0.17x PBS, 0.05% Tween-20,6mM DTT) Middle completion.All reactions carry out in 96 orifice plates of the polystyrene that final volume is 0.135mL.The orifice plate of test is even Hatch 1 hour under continuous concussion in room temperature condition, the magnetic bead of compatibility uses washing buffer (1x PBS, 0.05% Tween-20) Washing, is then resuspended to elution buffer (1x PBS, 0.05% Tween-20,0.5 μM of non-biotinylated affinity ligands) In, and hatch 30 minutes under continuous concussion in room temperature condition.Kinase concentration in eluent is measured by qPCR.

Kinase assay in the present invention is by the KINOMEscan of DiscoveRx company^TMAnalysis Service is completed (42501Albrae St.Fremont,CA94538,USA)。

Embodiment D: Xenograft Tumor Models

The drug effect of the compounds of this invention is evaluated by the standard Murine models of transplantation tumor.Human tumor cells (U87MG glioma cell, ATCC) culture after collecting, is inoculated in rear veutro in the female nude mice body of 6-7 week old (BALB/cA nu/nu, Hunan SLAC Animal Lab.) (for solvent group and each dosage group: n=6-10).When tumour body Product reaches 100-250mm³When, animal is randomly divided into solvent control group (5%DMSO+70%(30%), 7% HCl (pH1), 18%(30%)；Or 7%DMSO, 7%HCl (pH1), 70%(30%), 16%And compound group (30%)).It is subsequent that gastric infusion is carried out using compound on animals, it is connect from tumour cell Start from anywhere in 0 to 15 days after kind, and usually carries out daily in test primary.

Tumor growth inhibition (TGI) analysis

The crystallization growth of tumour is evaluated by the relationship of gross tumor volume and time.The long axis of subcutaneous tumor (L) it is measured weekly twice with short axle (W) by caliper, the volume (TV) of tumour passes through formula (L × W²)/2) it is calculated. TGI is calculated by the intermediate value of solvent group mouse tumor volume and the difference of medicine group mouse tumor volume-median, with solvent The percentage of control group gross tumor volume intermediate value indicates, is calculated by following formula:

Primary statistics analysis is by repeating variance measurement analysis (RMANOVA) come what is completed.Followed by Scheffe Psot hoc test method carries out Multiple range test.Separate solvent (5%DMSO+70%(30%), 7%HCl (pH1), 18%(30%)；Or 7%DMSO, 7%HCl (pH1), 70%(30%), 16%It (30%)) is negative control.

It is finally noted that there are also other ways, and the present invention can be implemented.Correspondingly, the embodiment of the present invention be by It is illustratively illustrated, but is not limited to content described in the invention, it is also possible to be repaired made by within the scope of the present invention Change or in the claims added by equivalent.All publications or patent cited in the present invention all will be as the present invention Bibliography.

Claims (21)

1. a kind of compound, be structure shown in formula (I) compound or formula (I) shown in compound it is pharmaceutically acceptable Salt:

Wherein:

X is H, C_1-12Alkyl, C_3-12Naphthenic base, C_6-12Aryl, 3-12 former molecular heterocycle or 5-12 original are molecular Heteroaryl, wherein each C_1-12Alkyl, C_3-12Naphthenic base, C_6-12Aryl, 3-12 former molecular heterocycle and 5-12 are a Former molecular heteroaryl is individually optionally by 1,2,3,4 or 5 R¹Replaced group；

R¹For H, F, Cl, Br, CN, NO₂, oxo (=O), OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4Alkylidene or C_1-6 Alkyl, wherein the C_1-6Alkyl is unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；

Y is monocycle or bicyclic system comprising at least one N atom, and the monocycle is armaticity, and the bicyclic system In at least one ring be armaticity, wherein the Y is optionally by 1,2,3,4 or 5 R²Replaced group；

R²For H, F, Cl, CN, oxo (=O), OR^a, NR^aR^b, R^aO-C_1-2Alkylidene, R^bR^aN-C_1-2Alkylidene, C_1-3Alkyl, C_2-4 Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, phenyl or 5 molecular heteroaryls of original, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, phenyl and 5 molecular heteroaryls of original are independently unsubstituted or by 1,2,3 or 4 substituent group Replaced, the substituent group is independently selected from F, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-2Alkylidene or R^bR^aN-C_1-2Alkylene Base；

When Y is 4- quinazolinone, R²It is not phenyl；

Each R³And R⁴It independently is H or C_1-6Alkyl；With

Each R^a, R^bAnd R^cIt independently is H or C_1-6Alkyl.

2. compound according to claim 1, wherein X C_1-6Alkyl, C_3-8Naphthenic base, C_6-10Aryl, 3-7 atom group At heterocycle or 5-10 former molecular heteroaryl, wherein each C_1-6Alkyl, C_3-8Naphthenic base, C_6-10Aryl, 3-7 The molecular heterocycle of a original and 5-10 former molecular heteroaryl it is individually optional by 1,2,3 or 4 R¹Replaced group.

3. compound according to claim 1, wherein R¹For H, F, Cl, CN, oxo (=O), OR^a, NR^aR^b, R^aO-C_1-4 Alkylidene, R^bR^aN-C_1-4Alkylidene or C_1-6Alkyl, wherein the C_1-6Alkyl is unsubstituted or by 1,2,3 or 4 substituent group institute Replace, the substituent group is independently selected from F, Cl, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylene Base.

4. compound according to claim 1, wherein Y is the bicyclic system comprising at least one N atom, and described At least one ring is armaticity in bicyclic system, wherein the Y is optionally by 1,2,3 or 4 R²Replaced group；Work as Y When for 4- quinazolinone, R²It is not phenyl.

5. compound according to claim 1, wherein each R³And R⁴It independently is H or C_1-4Alkyl.

6. compound according to claim 1, wherein X C_1-4Alkyl, C_3-6Naphthenic base, phenyl, 3-6 atom composition Heterocycle or 5-6 former molecular heteroaryl, wherein each C_1-4Alkyl, C_3-6Naphthenic base, phenyl, 3-6 atom group At heterocycle and 5-6 former molecular heteroaryl individually optionally by 1,2,3 or 4 R¹Replaced group.

7. compound according to claim 1, wherein R¹For H, F, Cl, CN, oxo (=O), OR^a, NR^aR^b, R^aO-C_1-2 Alkylidene, R^bR^aN-C_1-2Alkylidene or C_1-3Alkyl, wherein the C_1-3Alkyl is unsubstituted or by 1,2,3 or 4 substituent group institute Replace, the substituent group is independently selected from F, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-2Alkylidene or R^bR^aN-C_1-2Alkylidene.

8. compound according to claim 1, wherein Y is

Wherein, W independently is N or CH, and the Y is optionally by 1,2,3 or 4 R²Replaced group；When W is N, R²No For phenyl.

9. compound according to claim 1, wherein each R³And R⁴It independently is H or C_1-3Alkyl.

10. compound according to claim 1, wherein each R^a, R^bAnd R^cIt independently is H or C_1-3Alkyl.

11. compound according to claim 1, wherein Y is

Wherein, W CH, and the Y is optionally by 1,2 or 3 R²Replaced group.

12. compound according to claim 1, wherein Y is

Wherein, W N, and the Y is optionally by 1,2 or 3 R²Replaced group.

13. compound according to claim 1, the structure with one of:

14. a kind of pharmaceutical composition includes compound described in claim 1-13 any one and one or more pharmaceutically may be used The carrier of receiving, excipient, diluent, adjuvant, medium or their combination.

15. pharmaceutical composition according to claim 14 further includes one or more therapeutic agents.

16. pharmaceutical composition described in compound described in claim 1-13 any one or claim 14-15 any one Purposes in medicine preparation, wherein the drug is handled, treatment or mitigation PI3- kinases exception related disease for protecting.

17. purposes according to claim 16, wherein the PI3- kinases exception related disease is respiratory disease, disease Poison infection, non-viral respiratory tract infection, anaphylactia, autoimmune disease, inflammatory disease, cardiovascular disease are pernicious Blood disease, neurodegenerative disease, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, sperm motility, transplanting row Reprimand, graft rejection, injury of lungs or pain.

18. purposes according to claim 16, wherein the PI3- kinases exception related disease is asthma, chronic obstruction Property tuberculosis (COPD), viral respiratory infection, viral respiratory disease deteriorate, aspergillosis, leishmaniasis, allergia nose Inflammation, allergic dermatitis, rheumatic arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematologic Disease, neurodegenerative disease, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, sperm motility, graft rejection move Plant repels, injury of lungs, pain relevant to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain, after liver Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain.

19. pharmaceutical composition described in compound described in claim 1-13 any one or claim 14-15 any one The purposes of object in medicine preparation, the drug is for inhibiting PI3- kinase activity.

20. purposes according to claim 19, further including makes compound described in claim 1-13 any one Or pharmaceutical composition described in claim 14-15 any one is contacted with biological sample.

21. purposes according to claim 19, wherein the PI3- kinases is PI3K δ.